HIV protease inhibitors

ABSTRACT

The present invention relates to novel dihydropyrones with tethered heterocycles having improved pharmacologic properties which potently inhibit the HIV aspartyl protease blocking HIV infectivity. The dihydropyrones are useful in the development of therapies for the treatment of viral infections and diseases including AIDS. The present invention is also directed to methods of synthesis of the dihydropyrones and intermediates useful in the preparation of the final compounds.

BACKGROUND OF THE INVENTION

[0001] The HIV-protease enzyme is absolutely essential for thereplication and dissemination of HIV throughout the body (Navia M. A.and McKeever B. M., Ann. New York Acad. Sci., 1990;616:73-85) and hasbecome an extremely important target for the design and development ofanti-HIV therapeutic agents (von der Helm K., Biol. Chem.1996;377:756-774). Several peptidomimetic HIV protease inhibitors havebeen successfully developed (such as indinavir, saquinavir, ritonavir,and nelfinavir), which demonstrate significant clinical success inlowering plasma viral load, reducing the onset to AIDS, and decreasingthe frequency of opportunistic infections (Deeks S. G., Smith M.,Holodniy M., and Kahn J. O., JAMA., 1997;277:145-153).

[0002] Yet the current HIV protease inhibitors by their peptidomimeticnature have relatively poor solubility, high biliary excretion, limitedbioavailabilities and significant liver metabolism. These drawbacks inturn increase the need for high doses of drug which increases thefrequency of various side effects and multiple drug interactions (BarryM., Gibbons S., Back D., and Mulcahy F., Clin. Pharmacokinet.,1997;32:194-209). More importantly, resistance to the current HIVprotease inhibitors has emerged (Shock H. B., Garsky V. M., and Kuo L.,J. Biol. Chem., 1996;271:3 1957-3 1963) resulting in treatment failures(Fatkenheuer G., Theisen A., Rockstroh J., Grabow T., et al., AIDS,1997;11:F113-F116). From this discussion, it is apparent that while HIVprotease C is an excellent antiviral target for the treatment of HIVinfection and AIDS, there is a critical need to identify non-peptideinhibitors with improved pharmacological properties and which are notcross resistant with the current drugs (Wallace R. W., DDT,1997;2:83-84).

[0003] U.S. Pat. No. 5,789,440 recites non-peptidic HIV proteaseinhibitors of formula A

[0004] The patent application is hereby incorporated by reference.Excellent HIV protease inhibition was achieved, but the antiviralactivity at the cellular level was in some cases less than desired foran ideal therapeutic agent due to poor overall pharmacologicalproperties (Tummino P. J., Vara Prasad J. V. N., Ferguson D., Nauhan C.,et al., BioOrganic and Med. Chem., 1996;4:1401-1410). These effortshowever led to a core structure B where R₁ and R₂ were alkyl groupsfilling the

[0005] S₁′ and S₂′ pockets, respectively, and the phenyl of thephenethyl group at C₆ filled the S₂ pocket very efficiently. This corestructure was recognized as a valuable platform for additional study(Tait B. D., Hagen S., Domagala J. M., Ellsworth E. L., et al., J. Med.Chem., 1997;40:3781-3792).

[0006] Additional dihydropyrones C were reported when it wasunexpectedly discovered that certain polar groups judiciously placed atR₁-R₅ led to greatly

[0007] improved antiviral cellular activity. See U.S. patent applicationSer. No. 08/883,743. The patent application is hereby incorporated byreference. Among the preferred compounds were those where R₁ and R₅ wereOH, NH₁ or CH₂OH. In such cases, the preferred R₄ included a small alkylchain or ring and R₆ was methyl. In addition to improved cellularantiviral activity, the compounds also showed good pharmacokinetics inanimals relative to the non-polar substituted compounds. These compoundswere also not cross resistant with current HIV Protease inhibitors(Hagen S. E., Vara Prasad J. V. N., Boyer F. E., Domagala J. M., et al.,J. Med., 1997;40:3707-3711; Vander Roest S., Wold S., and Saunders J.,37th Interscience Conference on Antimicrobial Agents and Chemotherapy,Sep. 28-Oct. 1, 1997, Toronto, Canada. Abstract 1-84; Domagala J. M.,Boyer F., Ellsworth E., Gajda C., et al., 5^(th) Conference onRetroviruses and Opportunistic Infections, Feb. 1-5, 1998, Chicago, Ill.Abstract 638).

[0008] While the compounds C were notable for their improvedpharmacological properties relative to the non-polar substituted coremolecules B, these highly favorable properties were conferred directlyby the use of OH, NH₂ and NR₂ groups placed on the lipophilic rings. Therings themselves were important for binding to the enzyme “pockets” andfor holding the t-butyl group and the groups R₁-R₃ and R₅ in theirproper places within the enzyme's active site.

[0009] It is well-known in the pharmacological sciences that OH and NH₂groups, especially phenols and anilines, offer distinct metabolic sitesresulting in deactivation of the drug and more rapid clearance. Inparticular, phenols may be glucuronidated and amines and anilines aresubstrates for rapid acetylation (Goodman L. S. and Gilman A., ThePharmacological Basis of Therapeutics, Permagon Press, New York, N.Y.1985: 13-116). Such modifications generally inactivate the drug bypreventing its binding to the structurally stringent active site of theenzyme. The modifications also reduce the plasma level of the activeagent (Caldwell J., in Concepts in Drug Metabolism, edited by Jenner P.and Testa B., Marcel Dekker, New York, N.Y., Part A, 1980:235-238).Another suggested problem with amines and anilines is their possibleoxidation to electropositive nitrogen species which have mutagenicpotential (Sobels F. H. Mut. Res., 1985;157:107-110; Bus J. S. and PoppJ. A., Fd Chem. Toxic. 1987;25:619-626; Rodrigues-Arnaiz R. and ArandaJ. H., Env. Mol. Mutagenesis, 1994;24:75-79). Thus, while the polargroups are vital for good antiviral efficacy, solubility, and oralabsorption, they also present sites for metabolism and possiblemutagenesis.

[0010] This hereby incorporates by reference 5888L1-01-TMC filed on evendate herewith now U.S. Patent Application Serial No. 60/099,944 filedSep. 11, 1998, entitled “A Method of Making Dihydropyrone HIV ProteaseInhibitors” by Victor Fedij, et al.

SUMMARY OF THE INVENTION

[0011] The present invention relates to the extraordinary discovery thatthe phenyl groups bearing the important polar groups (especially the OHand NH₂ groups) in formula C above, the very polar groups that improvedcellular antiviral activity and improved pharmacokinetics in animalsrelative to compounds of formula B, can themselves be replaced bycertain selected heterocycles. These heterocycles bind to the enzyme inthe manner of the phenyls to preserve essential enzymatic activity, butadditionally present the polar atoms of the heterocycle in such a way asto maintain cellular antiviral activity without requiring peripheral OHand NH₂ groups. Since these compounds have fewer peripheral OH and NH₂groups, they have even greater pharmacokinetic improvements and lesspotential for amine based toxicity.

[0012] The dihydropyrones with selected heterocycles replacing thephenyls bearing polar substituents are useful in the development oftreatments for infections caused by viruses, especially by retrovirusesthat rely on aspartyl protease activities for replication andinfectivity. One such virus is HIV. These dihydropyrones provide higherplasma levels in animals and man due to reduced metabolism and/orclearance, and they provide less toxicity risk due to the removal ofcertain reactive anilino functionalities. For these reasons, thecompounds of this invention are very useful for lowering viral load inindividuals infected with HIV. Furthermore, the compounds reducediseases and syndromes associated with viral pathogenesis. One suchsyndrome is AIDS.

[0013] The compounds of the instant invention will be useful accordingto: Guidelines for the Use of Antiretroviral Agents in HIV-InfectedAdults and Adolescents, supplement to the J. of the InternationalAssociation of Physicians in AIDS Care, Supp. No. 1, Vol. 5, pp 4-26 andDavid A. Katzenstein, Antiretroviral Therapy for HIV: What to do in1999. The Journal of Critical Illness, April 1999;14(4):196.

DETAILED DESCRIPTION OF THE INVENTION

[0014] The present invention relates to compounds or pharmaceuticallyacceptable salts thereof, of Formula I

[0015] R₁ is H, a straight or branched alkyl of 1-6 carbons or acarbocycle of 3-6 carbons;

[0016] R₂ is H, a straight or branched alkyl of 1-5 carbons;

[0017] R₃ is H, (CR′₂)_(n)OR, (CR′₂)_(n)N(R)₂, (CR′₂)_(n)NR′COR,(CR′₂)_(n)CO₂R, (CR′₂)_(n)OCOR, (CR′₂)_(n)CON(R)₂, (CR′₂)_(n)OCON(R)₂,(CR′₂)_(n)R, (CR′₂)_(n)NR′CON(R)₂, (CR′₂)_(n)NR′CO₂R,(CR′₂)_(n)OSO₂N(R)₂, (CR′₂)_(n)NR′SO₂OR, (CR′₂)_(n)NR′SO₂N(R)₂,(CR′₂)_(n)OSO₂R, (CR′₂)_(n)NR′SO₂R, (CR′₂)_(n)SO_(p)R,(CR′₂)_(n)NR′CSN(R)₂, (CR′₂)_(n)NR′C(NR′)N(R)₂, (CR′₂)_(n)SO₂N(R)₂,(CR′₂)_(n)C(NR′)N(R)₂, (CR′₂)_(n)COR, O(CR′₂)_(m)OR, NR(CR′₂)_(m)OR, F,Cl, Br, CF₃, CN, or ═O;

[0018] R₄, R₅, and R₆ are independently H, a straight or branched alkylof 1-6 carbons, a cycloalkyl of 3-6 carbons, (CR′₂)_(n)OR,(CR′₂)_(n)N(R)₂, F, Cl, Br, CN, CF₃, ═O, (CR′₂)_(p)NR′COR,(CR′₂)_(p)SO_(p)R, (CR′₂)_(p)R, (CR′₂)_(p)OCOR, O(CR′₂)_(m)OR,NR(CR′₂)_(m)OR, (CR′₂)_(p)NR′CON(R)₂, (CR′₂)_(p)OCON(R)₂,(CR′₂)_(p)NR′CO₂R,(CR′₂)_(p)COR, (CR′₂)_(p)CO₂R, (CR′₂)_(p)CON(R)₂,(CR′₂)_(p)NR′SO₂R, (CR′₂)_(p)SO₂N(R)₂, (CR′₂)_(p)NR′SO₂OR,(CR′₂)_(p)OSO₂N(R)₂, (CR′₂)_(p)NR′SO₂N(R)₂, (CR′₂)_(p)C(NR′)N(R)₂,(CR′₂)_(p)NR′C(NR′)N(R)₂ (CR′₂)_(p)Het;

[0019] any two of R₁—R₃ or R₄-R₆ may together form a ring of 5-6 totalatoms which may contain 0-3 heteroatoms;

[0020] n is an integer of from 0 to 3;

[0021] m is an integer of from 2 to 4;

[0022] p is an integer from 0 to 2;

[0023] R₇ is a straight or branched alkyl of 1-6 carbons or a carbocycleof 3-6 carbons;

[0024] R is independently H, a straight or branched alkyl of 1-4carbons, (CH₂)_(n)Ph, or a (CH₂)_(n)heterocycle of 5-6 atoms containing1-2 heteroatoms and wherein the (R)₂ in N(R)₂ may form a heterocyclecontaining the nitrogen, all optionally substituted by F, Cl, Br, OR′,CN, CO₂R′, N(R′)₂, NR′COR′, CF₃, or ═O;

[0025] R′ is independently H, a straight or branched alkyl of 1-4carbons, or phenyl;

[0026] R″ is independently H, a straight or branched alkyl of 1-4carbons, F, Cl, Br, OR′, or N(R′)₂;

[0027] Ar₁ and Ar₂ are independently phenyl or Het with the proviso thatat least one Ar is Het;

[0028] Het is a heterocycle of from 5-6 atoms having from 1-4heteroatoms or a fused heterocycle of from 9-10 atoms having 1-3heteroatoms.

[0029] A compound which upon administering to a human being convertsinto a compound according to Formula I is within the scope of thisinvention.

[0030] Preferred compounds of Formula I are those wherein:

[0031] R₁ is isopropyl or t-butyl;

[0032] R₂ is H, methyl, or ethyl;

[0033] R₃ is H, (CR′₂)_(n)OR, (CR′₂)_(n)N(R)₂, (CR′₂)_(n)NR′COR,(CR′₂)_(n)CO₂R, (CR′₂)_(n)OCOR, (CR′₂)_(n)CON(R)₂, (CR′₂)_(n)OCON(R)₂,(CR′₂)_(n)NR′CON(R)₂, (CR′₂)_(n)NR′CO₂R, (CR′₂)_(n)OSO₂N(R)₂,(CR′₂)_(n)NR′SO₂OR, (CR′₂)_(n)NR′SO₂N(R)₂, (CR′₂)_(n)OSO₂R,(CR′₂)_(n)NR′SO₂R, (CR′₂)_(n)SO_(p)R, (CR′₂)_(n)NR′CSN(R)₂,(CR′₂)_(n)COR, O(CR′₂)_(m)OR, NR(CR′₂)_(m)OR, F, Cl, Br, CF₃, CN, or ═O;

[0034] R₄, R₅, and R₆ are independently H, a straight or branched alkylof 1-6 carbons, a cycloalkyl of 3-6 carbons, (CH₂)_(n)OR,(CH₂)_(n)N(R)₂, F, Cl, Br, CN, CF₃, ═O, (CR′₂)_(p)NR′COR,(CR′₂)_(p)SO_(p)R, (CR′₂)_(p)NR′CON(R)₂, (CR′₂)_(p)OCON(R)₂,(CR′₂)_(p)NR′CO₂R, (CR′₂)_(p)COR, (CR′₂)_(p)CO₂R, (CR′₂)_(p)CON(R)₂,(CR′₂)_(p)NR′SO₂R, (CR′₂)_(p)SO₂N(R)₂, (CR′₂)_(p)NR′SO₂OR,(CR′₂)_(p)OSO₂N(R)₂, (CR′₂)_(p)Het and any two of R₁-R₃ or R₄-R₆ maytogether form a ring of 5-6 total atoms which may contain 0-2heteroatoms;

[0035] n is an integer of 0 to 3;

[0036] m is an integer of 2 to 4;

[0037] p is 0 to 2;

[0038] R₇ is a straight or branched alkyl of 1-6 carbons or a carbocycleof 3-6 carbons;

[0039] R is H, a straight or branched alkyl of 1-4 carbons, (CH₂)_(n)Ph,or a (CH₂)_(n)heterocycle of 5-6 atoms containing 1-2 heteroatoms andwherein the (R)₂ in N(R)₂ may form a heterocycle containing thenitrogen, all optionally substituted by F, Cl, Br, OR′, N(R′)₂, NR′COR′,CF₃, or ═O—;

[0040] R′ is H, a straight or branched alkyl of 1-4 carbons, or phenyl;

[0041] R″ is H, a straight or branched alkyl of 1-4 carbons, F, Cl, Br,OR′, or N(R′)₂;

[0042] Ar₁ is phenyl or Het; and

[0043] Ar₂ is Het wherein Het is a heterocycle of from 5-6 atoms having1-4 heteroatoms selected from: furan, pyrrole, thiophene, oxazole,isoxazole, thiazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole,tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, tetrahydrofuran,tetrahydrothiophene, pyrrolidine, piperazine, piperidine, morpholine,thiomorpholine, oxolane, dioxane, sulfolane; or a fused heterocycle offrom 9-10 atoms having from 1-3 heteroatoms selected from: benzofuran,indole, indoline, benzothiophene, benzimidazole, benzthiazole,benzoxazole, quinoline, isoquinoline, cinnoline, quinazoline andquinoxaline

[0044] Other preferred compounds of Formula I are those wherein:

[0045] R₁ is isopropyl or t-butyl;

[0046] R₂ is H, methyl or ethyl;

[0047] R₃ is H, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, (CH₂)_(n)NR′COR,(CH₂)_(n)CON(R)₂, (CH₂)_(n)OCON(R)₂, (CH₂)_(n)NR′CON(R)₂,(CH₂)_(n)NR′CO₂R, (CH₂)_(n)OSO₂N(R)₂, (CH₂)_(n)NR′SO₂OR,(CH₂)_(n)NR′SO₂N(R)₂, (CH₂)_(n)OSO₂R, (CH₂)_(n)NR′SO₂R, (CH₂)_(n)SO₂R,(CH₂)_(n)NR′CSN(R)₂, (CH₂)_(n)COR, O(CH₂)_(m)OR′, NR(CH₂)_(m)OR′, orC(CH₃)₂OR′;

[0048] R₄, R₅, and R₆ are independently H, a straight or branched alkylof 1-6 carbons, a cycloalkyl of 3-6 carbons, (CH₂)_(n)OR,(CH₂)_(n)N(R)₂, F, Cl, Br, CN, CF₃, ═O, (CH₂)_(p)NR′COR,(CH₂)_(p)NR′CON(R)₂, (CH₂)_(p)OCON(R)₂, (CH₂)_(p)NR′CO₂R, (CH₂)_(p)COR,(CH₂)_(p)CON(R)₂, (CH₂)_(p)NR′SO₂R, (CH₂)_(p)NR′SO₂OR,(CH₂)_(p)OSO₂N(R)₂, wherein p is 0 to 2, or R₄ and R₅ may together forma ring of 5-6 total atoms which may contain 0-2 heteroatoms;

[0049] n is an integer of 0 to 3;

[0050] m is an integer of 2 to 4;

[0051] R₇ is a straight or branched alkyl of 1-6 carbons or a carbocycleof 3-6 carbons;

[0052] R is H, a straight or branched alkyl of 1-4 carbons, (CH₂)_(n)Ph,or a (CH₂)_(n)heterocycle of 5-6 atoms containing 1-2 heteroatoms andwherein the (R)₂ in N(R)₂ may be a heterocycle containing the nitrogen,all optionally substituted by F, Cl, Br, OR′, N(R′)₂, NR′COR′, or ═O;

[0053] R′ is H, a straight or branched alkyl of 1-4 carbons, or phenyl;

[0054] R″ is H, a straight or branched alkyl of 1-4 carbons, F, Cl, Br,OR′, or N(R′)₂;

[0055] Ar₁ is phenyl; and

[0056] Ar₂ is a heterocycle of 5-6 atoms having from 1-4 heteroatomsselected from: furan, pyrrole, thiophene, oxazole, isoxazole, thiazole,pyrazole. 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine,pyridazine, pyrimidine, pyrazine, tetrahydrofuran, tetrahydrothiophene,pyrrolidine, piperazine, piperidine, morpholine, thiomorpholine,oxolane, dioxane, sulfolane; or a fused heterocycle of 9-10 atoms havingfrom 1-3 heteroatoms selected from: benzofuran, indole, indoline,benzothiophene, benzimidazole, benzthiazole, benzoxazole, quinoline,isoquinoline, cinnoline, quinazoline and quinoxaline.

[0057] Still other preferred compounds of Formula I are those wherein:

[0058] R₁ is H, a straight or branched alkyl of 1-6 carbons or acarbocycle of 3-6 carbons;

[0059] R₂ is H, a straight or branched alkyl of 1-5 carbons;

[0060] R₃ is H, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, (CH₂)_(n)NR′COR,(CH₂)_(n)CON(R)₂, (CH₂)_(n)OCON(R)₂, (CH₂)_(n)NR′CON(R)₂(CH₂)_(n)NR′CO₂R, (CH₂)_(n)OSO₂N(R)₂, (CH₂)_(n)NR′SO₂OR,(CH₂)_(n)NR′SO₂N(R)₂, (CH₂)_(n)OSO₂R, (CH₂)_(n)NR′SO₂R, (CH₂)_(n)SO₂R,(CH₂)_(n)COR, O(CH₂)_(m)OR, NR(CH₂)_(m)OR, C(CH₃)₂OR′, F, Cl, Br, CF₃,or ═O;

[0061] R₄, R₅, and R₆ are independently H, a straight or branched alkylof 1-6 carbons, a cycloalkyl of 3-6 carbons, (CH₂)_(n)OR,(CH₂)_(n)N(R)₂, F, Cl, Br, ═O, (CH₂)_(p)NR′COR, (CH₂)_(p)NR′CON(R)₂,(CH₂)_(p)OCON(R)₂, (CH₂)_(p)NR′CO₂R, (CH₂)_(p)COR, (CH₂)_(p)CON(R)₂,(CH₂)_(p)NR′SO₂R, (CH₂)_(p)NR′SO₂OR, (CH₂)_(p)OSO₂N(R)₂, wherein p is 0to 2;

[0062] R₄ and R₅ may together form a ring of 5-6 total atoms which maycontain 0-2 heteroatoms;

[0063] n is an integer of 0 to 3;

[0064] m is an integer of 2 to 4;

[0065] R₇ is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl;

[0066] R is H, a straight or branched alkyl of 1-4 carbons, (CH₂)_(n)Ph,or a (CH₂)_(n)heterocycle of 5-6 atoms containing 1-2 heteroatoms andwherein the (R)₂ in N(R)₂ may be a heterocycle containing the nitrogen,all optionally substituted by F, Cl, Br, OR′, N(R′)₂, NR′COR′, or ═O;

[0067] R′ is H, a straight or branched alkyl of 1-4 carbons, or phenyl;

[0068] R″ is H, a straight or branched alkyl of 1-4 carbons, F, Cl, Br,OR′, or N(R′)₂;

[0069] Ar₁ is phenyl or Het; and

[0070] Ar₂ is Het wherein Het is a heterocycle of 5-6 atoms having from1-4 heteroatoms selected from: furan, pyrrole, thiophene, oxazole,isoxazole, thiazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole,tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, tetrahydrofuran,tetrahydrothiophene, pyrrolidine, piperazine, piperidine, morpholine,thiomorpholine, oxolane, dioxane, sulfolane; or a fused heterocycle offrom 9-10 atoms having 1-3 heteroatoms selected from: benzofuran,indole, indoline, benzothiophene, benzimidazole, benzthiazole,benzoxazole, quinoline, isoquinoline, cinnoline, quinazoline andquinoxaline.

[0071] Still other preferred compounds of Formula I are those wherein:

[0072] R₁ is H, methyl, ethyl, isopropyl, or t-butyl;

[0073] R₂ is H or methyl;

[0074] R₃ is H, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, (CH₂)_(n)NR′COR,(CH₂)_(n)CON(R)₂, (CH₂)_(n)OCON(R)₂, (CH₂)_(n)NR′CON(R)₂,(CH₂)_(n)NR′CO₂R, (CH₂)_(n)OSO₂N(R)₂, (CH₂)_(n)NR′SO₂OR,(CH₂)_(n)NR′SO₂N(R)₂, (CH₂)_(n)OSO₂R, (CH₂)_(n)NR′SO₂R, (CH₂)_(n)SO₂R,(CH₂)_(n)COR, O(CH₂)_(m)OR′, NR(CH₂)_(m)OR′, C(CH₃)₂OR′, F, Cl, Br, CF₃,or ═O;

[0075] R₄, R₅, and R₆ are independently H, a straight or branched alkylof 1-6 carbons, a cycloalkyl of 3-6 carbons, (CH₂)_(n)OR,(CH₂)_(n)N(R)₂, F, Cl, Br, CF₃, (CH₂)_(p)NR′COR, (CH₂)_(p)NR′CON(R)₂,(CH₂)_(p)OCON(R)₂, (CH₂)_(p)NR′CO₂R, (CH₂)_(p)COR, (CH₂)_(p)CON(R)₂,(CH₂)_(p)NR′SO₂R, (CH₂)_(p)NR′SO₂OR, (CH₂)_(p)OSO₂N(R)₂, (CH₂)_(p)Hetwherein p is 0 to 2;

[0076] any two of R₄-R₆ may together form a ring of 5-6 total atomswhich may contain 0-2 heteroatoms;

[0077] n is an integer of 0 to 3;

[0078] m is an integer of 2 to 4;

[0079] R₇ is a straight or branched alkyl of 1-6 carbons or a carbocycleof 3-6 carbons;

[0080] R is H, a straight or branched alkyl of 1-4 carbons, (CH₂)_(n)Ph,or a (CH₂)_(n)heterocycle of 5-6 atoms having from 1-2 heteroatoms andwherein the (R)₂ in N(R)₂ may form a heterocycle having nitrogen, alloptionally substituted by F, Cl, Br, OR′, N(R′)₂, NR′COR′, or ═O;

[0081] R′ is H, a straight or branched alkyl of 1-4 carbons, or phenyl;

[0082] R″ is H, a straight or branched alkyl of 1-4 carbons, F, Cl, Br,OR′, or N(R′)₂;

[0083] Ar₁ is a heterocycle of 5-6 atoms having from 1-4 heteroatomsselected from: furan, pyrrole, thiophene, oxazole, isoxazole, thiazole,pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine,pyridazine, pyrimidine, pyrazine, tetrahydrofuran, tetrahydrothiophene,pyrrolidine, piperazine, piperidine, morpholine, thiomorpholine,oxolane, dioxane, sulfolane; or a fused heterocycle of 9-10 atoms having1-3 heteroatoms selected from: benzofuran, indole, indoline,benzothiophene, benzimidazole, benzthiazole, benzoxazole, quinoline,isoquinoline, cinnoline, quinazoline and quinoxaline; and

[0084] Ar₂ is phenyl.

[0085] More preferred compounds of Formula I are those wherein:

[0086] R₁ is isopropyl or t-butyl;

[0087] R₂ is H or methyl;

[0088] R₃ is H, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, (CH₂)_(n)OCON(R)₂,(CH₂)_(n)NR′CON(R)₂, (CH₂)_(n)NR′CO₂R, (CH₂)_(n)OSO₂N(R)₂,(CH₂)_(n)NR′SO₂OR, (CH₂)_(n)NR′SO₂N(R)₂, (CH₂)_(n)NR′SO₂R,(CH₂)_(n)SO₂R, O(CH₂)_(m)OR′, NR(CH₂)_(m)OR′, or C(CH₃)₂OR′;

[0089] R₄, R₅, and R₆ are independently H, a straight or branched alkylof 1-6 carbons, a cycloalkyl of 3-6 carbons, (CH₂)_(n)OR,(CH₂)_(n)N(R)₂, F, Cl, Br, ═O, (CH₂)_(p)NR′COR, (CH₂)_(p)NR′CON(R)₂,(CH₂)_(p)OCON(R)₂, (CH₂)_(p)NR′COR, (CH₂)_(p)COR, (CH₂)_(p)CON(R)₂,(CH₂)_(p)NR′SO₂R, (CH₂)_(p)NR′SO₂OR, (CH₂)_(p)OSO₂N(R)₂, wherein p is 0to 2;

[0090] R₄ and R₅ may together form a ring of 5-6 total atoms which maycontain 0-2 heteroatoms;

[0091] n is an integer of 0 to 3;

[0092] m is an integer of 2 to 4;

[0093] R₇ is a straight or branched alkyl of 1-6 carbons or a carbocycleof 3-6 carbons;

[0094] R is H, a straight or branched alkyl of 1-4 carbons, (CH₂)_(n)Ph,or a (CH₂)_(n)heterocycle of 5-6 atoms having from 1-2 heteroatoms andwherein the (R)₂ in N(R)₂ may be a heterocycle containing the nitrogen,all optionally substituted by F, Cl, Br, OR′, N(R′)₂, NR′COR′, or ═O;

[0095] R′ is H, a straight or branched alkyl of 1-4 carbons, or phenyl;

[0096] R″ is H, a straight or branched alkyl of 1-4 carbons, F, Cl, Br,OR′, or N(R′)₂;

[0097] Ar₁ is phenyl; and

[0098] Ar₂ is furan, pyrrole, thiophene, oxazole, isoxazole, thiazole,pyrazole, tetrazole, or pyridine.

[0099] Other more preferred compounds of Formula I are those wherein:

[0100] R₁ is H, a straight or branched alkyl of 1-6 carbons or acarbocycle of 3-6 carbons;

[0101] R₂ is H, methyl or ethyl or isopropyl;

[0102] R₃ is H, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, (CH₂)_(n)NRCOR,(CH₂)_(n)CON(R)₂, (CH₂)_(n)OCON(R)₂, (CH₂)_(n)NR′CON(R)₂.(CH₂)_(n)NR′CO₂R, (CH₂)_(n)OSO₂N(R)₂, (CH₂)_(n)NR′SO₂OR,(CH₂)_(n)NR′SO₂N(R)₂, (CH₂)_(n)OSO₂R, (CH₂)_(n)NR′SO₂R, (CH₂)_(n)SO₂R,O(CH₂)_(m)OR, NR(CH₂)_(m)OR′, C(CH₃)₂OR′, or ═O;

[0103] R₄, R₅, and R₆ are independently H, a straight or branched alkylof 1-6 carbons, a cycloalkyl of 1-6 carbons, (CH₂)_(n)OR,(CH₂)_(n)N(R)₂, F, Cl, Br, ═O, (CH₂)_(p)NR′COR, (CH₂)_(p)NR′CON(R)₂,(CH₂)_(p)OCON(R)₂, (CH₂)_(p)NR′CO₂R, (CH₂)_(p)COR, (CH₂)_(p)CON(R)₂,(CH₂)_(p)NR′SO₂R, (CH₂)_(p)NR′SO₂OR, (CH₂)_(p)OSO₂N(R)₂, wherein p is 0to 2;

[0104] R₄ and R₅ may together form a ring of 5-6 total atoms which maycontain 0-2 heteroatoms;

[0105] n is an integer of 0 to 3;

[0106] m is an integer of 2 to 4;

[0107] R₇ is a straight or branched alkyl of 1-6 carbons or a carbocycleof 3-6 carbons;

[0108] R is H, a straight or branched alkyl of 1-4 carbons, (CH₂)_(n)Ph,or a (CH₂)_(n)heterocycle of 5-6 atoms containing 1-2 heteroatoms andwherein the (R)₂ in N(R)₂ may be a heterocycle having nitrogen, alloptionally substituted by F, Cl, Br, OR′, N(R′)₂, NR′COR′, or ═O;

[0109] R′ is H, a straight or branched alkyl of 1-4 carbons, or phenyl;

[0110] R″ is H, a straight or branched alkyl of 1-4 carbons, F, Cl, Br,OR′, or N(R′)₂;

[0111] Ar₁ is thiophene, thiazole, pyridine, benzothiophene,benzthiazole, benzoxazole, quinoline or isoquinoline; and

[0112] Ar₂ is phenyl or Het wherein Het is a heterocycle of 5-6 atomshaving from 1-4 heteroatoms selected from: furan, pyrrole, thiophene,oxazole, isoxazole, thiazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole,tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, tetrahydrofuran,tetrahydrothiophene, pyrrolidine, piperazine, piperidine, morpholine,thiomorpholine, oxolane, dioxane, sulfolane; or a fused heterocycle of9-10 atoms having 1-3 heteroatoms selected from: benzofuran, indole,indoline, benzothiophene, benzimidazole, benzthiazole, benzoxazole,quinoline, isoquinoline, cinnoline, quinazoline and quinoxaline.

[0113] Still other more preferred compounds of formula IV are thosewherein:

[0114] R₁ is isopropyl or t-butyl;

[0115] R₂ is H, methyl, or ethyl;

[0116] R₃ is CH₂OH, NH₂, OCH₂CH₂OH, NHCOR, OSO₂N(R)₂, NR′SO₂OR, NR′SO₂R,or OSO₂R;

[0117] R₄, R₅ and R₆ are independently H a straight or branched alkyl of1-6 carbons, a cycloalkyl of 1-6 carbons, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂,F, Cl, Br, ═O, (CH₂)_(p)NR′COR, (CH₂)_(p)NR′CON(R)₂, (CH₂)_(p)OCON(R),(CH₂)_(p)NR′CO₂R, (CH₂)_(p)COR, (CH₂)_(p)CON(R)₂, (CH₂)_(p)NR′SO₂R,(CH₂)_(p)NR′SO₂OR, (CH₂)_(p)OSO₂N(R)₂, wherein p is 0 to 2;

[0118] R₄ and R₅ may together form a ring of 5-6 total atoms which maycontain 0-2 heteroatoms;

[0119] R₇ is a straight or branched alkyl of 1-6 carbons or a carbocycleof 3-6 carbons,

[0120] R is H, a straight or branched alkyl of 1-4 carbons, (CH₂)_(n)Ph,or a (CH₂)_(n)heterocycle of 5-6 atoms having from 1-2 heteroatoms andwherein the (R)₂ in N(R)₂ may be a heterocycle having nitrogen, alloptionally substituted by F, Cl, Br, OR′, N(R′)₂, NR′COR′, or ═O;

[0121] R′ is H, a straight or branched alkyl of 1-4 carbons, or phenyl;

[0122] R″ is H, a straight or branched alkyl of from 1-4 carbons, F, Cl,Br, OR′, or N(R′)₂;

[0123] Ar₁ is phenyl; and

[0124] Ar₂ is a heterocycle of 5-6 atoms having from 1-4 heteroatomsselected from: furan, pyrrole, thiophene, oxazole, isoxazole, thiazole,pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine,pyridazine, pyrimidine, pyrazine, tetrahydrofuran, tetrahydrothiophene,pyrrolidine, piperazine, piperidine, morpholine, thiomorpholine,oxolane, dioxane, sulfolane; or a fused heterocycle of 9-10 atoms havingfrom 1-3 heteroatoms selected from: benzofuran, indole, indoline,benzothiophene, benzimidazole, benzthiazole, benzoxazole, quinoline,isoquinoline, cinnoline, quinazoline and quinoxaline.

[0125] Still other more preferred compounds of Formula I are thosewherein;

[0126] R₁ is H, methyl, ethyl, isopropyl, or t-butyl;

[0127] R₂ is H or methyl;

[0128] R₃ is H, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, (CH₂)_(n)NR′COR,(CH₂)_(n)CON(R)₂ (CH₂)_(n)OCON(R)₂, (CH₂)_(n)NR′CON(R),(CH₂)_(n)NR′CO₂R, (CH₂)_(n)OSO₂N(R)₂, (CH₂)_(n)NR′SO₂OR,(CH₂)_(n)NR′SO₂N(R)₂. (CH₂)_(n)OSO₂R, (CH₂)_(n)NR′SO₂R, (CH₂)_(n)SO₂R,(CH₂)_(n)NR′CSN(R)₂, (CH₂)_(n)COR, O(CH₂)_(m)OR, NR(CH₂)_(m)OR′,C(CH₃)₂OR′, F, Cl, Br, or ═O;

[0129] R₄, R₅ and R₆ are independently H, methyl, ethyl, OH, CH₂OH,CH₂CH₂OH, F, Cl, NH₂;

[0130] any two R₄-R₆ may form a ring of 5-6 atoms having from 1-2heteroatoms;

[0131] n is an integer of 0 to 3;

[0132] m is an integer of 2 to 4;

[0133] R₇ is a straight or branched alkyl of 1-6 carbons or a carbocycleof 3-6 carbons;

[0134] R is H, a straight or branched alkyl of 1-4 carbons, (CH₂)_(n)Ph,or a (CH₂)_(n)heterocycle of 5-6 atoms having from 1-2 heteroatoms or aheterocycle having a nitrogen, all optionally substituted by F, Cl, Br,OR′, N(R′)₂, NR′COR′, or ═O;

[0135] R′ is H, a straight or branched alkyl of 1-4 carbons, or phenyl;

[0136] R″ is H, a straight or branched alkyl of 1-4 carbons, F, Cl, Br,OR′, or N(R′)₂;

[0137] Ar₁ is furan, thiophene, thiazole, pyridine, imidazole,benzofuran, benzothiophene, benzimidazole, benzthiazole, quinoline, orisoquinoline; and

[0138] Ar₂ is phenyl.

[0139] Still other more preferred compounds of formula IV are thosewherein:

[0140] R₁ is H, methyl, ethyl, isopropyl, or t-butyl;

[0141] R₂ is H or methyl;

[0142] R₃ is H, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, or ═O; R₄, R₅, and R₆ areindependently H, methyl, OH, CH₂OH, CH₂CH₂OH, NH₂, or F;

[0143] R₇ is H, isopropyl, butyl, sec-butyl, cyclobutyl, cyclopentyl, orcyclohexyl;

[0144] R is H, methyl, ethyl, phenyl, or CH₂Ph and wherein the (R)₂ ofN(R)₂ may be a heterocycle having a nitrogen;

[0145] R″ is H, F, or CH₃;

[0146] Ar₁ is furan, thiophene, thiazole, pyridine, imidazole,benzofuran, benzothiophene, benzimidazole, benzthiazole, quinoline, orisoquinoline; and

[0147] Ar₂ is phenyl.

[0148] Most preferred compounds of Formula I are those wherein:

[0149] R₁ is H, methyl, ethyl, isopropyl, or t-butyl;

[0150] R₂ is H, methyl, ethyl, or isopropyl;

[0151] R₃ is H, NH₂, OH, CH₂OR, CH₂N(R)₂, CH₂CON(R)₂, CH₂OSO₂N(R)₂,CH₂NHSO₂OR, CH₂NHSO₂R, CH₂OSO₂R, Cl, Br, or OCH₂CH₂OH;

[0152] R₄, R₅, and R₆ are independently H, methyl, ethyl, isopropyl, OH,NH₂, CH₂OR, CH₂N(R)₂, ═O, F, Cl, Br, or CH₂NRCOR;

[0153] R₇ is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, orcyclopentyl;

[0154] R is H, methyl, ethyl, Ph, CH₂Ph, and wherein the (R)₂ in N(R)₂may be a heterocycle having a nitrogen;

[0155] R″ is H, F, or CH₃;

[0156] Ar₁ is thiophene, thiazole, furan, pyridine, benzothiophene,benzofuran, benzthiazole, benzoxazole, quinoline, or isoquinoline; and

[0157] AR₂ is furan, thiophene, oxazole, isoxazole, imidazale, thiazole,pyrazole, pyridine, benzofuran, benzothiophene, benzimidazole,benzthiazole, quinoline, or isoquinoline.

[0158] Other most preferred compounds of Formula I are those wherein:

[0159] R₁ is isopropyl or t-butyl;

[0160] R₂ is H, methyl, or ethyl;

[0161] R₃ is H, NH₂, OH, CH₂OR, CH₂N(R)₂, CH₂CON(R)₂, OSO₂N(R)₂,NHSO₂OR, NHSO₂R, OSO₂R, or OCH₂CH₂OH;

[0162] R₄, R₅, and R₆ are independently H, methyl, ethyl, isopropyl, OH,NH₂ CH₂OR; CH₂N(R)₂, ═O, F, Cl, Br, or CH₂NRCOR;

[0163] R₇ is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, orcyclopentyl;

[0164] R is H, methyl, ethyl, Ph, CH₂Ph, and wherein the (R)₂ in N(R)₂may be a heterocycle containing the nitrogen;

[0165] R″ is H, F, or CH₃;

[0166] Ar₁ is phenyl; and

[0167] Ar₂ is furan, thiophene, oxazole, isoxazole, imidazale, thiazole,pyrazole, pyridine, benzofuran, benzothiophene, benzimidazole,benzthiazole, quinoline, or isoquinoline.

[0168] Still other most preferred compounds of Formula I are thosewherein:

[0169] R₁ is isopropyl or t-butyl;

[0170] R₂ is H, methyl, or ethyl;

[0171] R₃ is NH₂, CH₂OH, OCH₂CH₂OH, or CH₂CH₂OH;

[0172] R₄, R₅, and R₆ are independently H, NH₂, CH₂OH, ═O, methyl,ethyl, or isopropyl;

[0173] R₇ is isopropyl;

[0174] R″ is H, F, or CH₃;

[0175] Ar₁ is phenyl; and

[0176] Ar₂ is furan, thiophene, imidazole, thiazole, pyrazole, orpyridine.

[0177] Still other most preferred compounds of Formula I are thosewherein:

[0178] R₁ is H, methyl, ethyl, isopropyl, or t-butyl;

[0179] R₂ is H or methyl;

[0180] R₃ is H, CH₂OH, NH₂, or ═O;

[0181] R₄, R₅, and R₆ are independently H, OH, CH₂OH, NH₂, or F;

[0182] R₇ is isopropyl, sec-butyl, isobutyl, or cyclopentyl;

[0183] R is H, methyl, ethyl, Ph, CH₂Ph, and wherein the (R)₂ in N(R)₂may be a heterocycle having a nitrogen;

[0184] R″ is H, F, or CH₃;

[0185] Ar₁ is furan, thiophene, imidazole, thiazole, pyrazole, orpyridine; and

[0186] Ar₂ is phenyl.

[0187] Especially preferred compounds of the invention are:

[0188]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-pyridin-4-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0189]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-pyridin-3-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0190]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-pyridin-2-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0191]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-6-(2-furan-3-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0192]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-6-(2-furan-2-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0193]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(tetrahydro-furan-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0194]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0195]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-2-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0196]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(5-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0197]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0198]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0199](S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-isopropyl-6-phenethyl-5,6-dihydro-pyran-2-one;

[0200](S)-3-(2-Amino-5-isopropyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-isopropyl-6-phenethyl-5,6-dihydro-pyran-2-one;

[0201]6-[-2-(4-Fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-3-(5-isopropyl-benzothiazol-6-ylsulfanyl)-5,6-dihydro-pyran-2-one;

[0202]3-(2-Amino-5-isopropyl-benzothiazol-6-yl-sulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-phenethyl-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0203](S)-3-(2-Amino-7-isopropyl-4-methyl-benzothiazol-6-yl-sulfanyl)-4-hydroxy-6-isopropyl-6-phenethyl-5,6-dihydro-pyran-2-one;

[0204](S)-3-(2-Amino-7-isopropyl-4-methyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-[2-(4-hydroxyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0205](S)-(6-{4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-4-isopropyl-7-methyl-benzothiazol-2-yl)-carbamicacid methyl ester;

[0206](S)-3-(2-Amino-6-tert-butyl-benzothiazol-4-ylsulfanyl)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0207](S)-3-(3-tert-Butyl-benzo[b]thiophen-2-ylsulfanyl)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0208]3-(3-tert-Butyl-benzo[b]thiophen-2-yl-sulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0209]4-Hydroxy-3-(5-hydroxymethyl-2-isopropyl-thiophen-3-ylsulfanyl)-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0210]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiazol-5-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0211]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiazol-2-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0212]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiazol-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0213]N-(4-{2-[5-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-2-isopropyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-thiazol-2-yl)-acetamide;

[0214]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(5-methyl-thiazol-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0215]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiazol-5-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0216]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(2-methyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0217]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(5-methyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0218]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(2-isopropyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0219]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-isopropyl-thiazol-5-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0220]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(5-isopropyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0221]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0222]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-6-(2-furan-3-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0223]3-(2-tert-Butyl-4-hydroxy-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(5-hydroxymethyl-thiophen-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0224]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(5-hydroxymethyl-thiophen-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0225]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(5-hydroxymethyl-thiophen-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0226]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(1H-pyrazol-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0227]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-[2-(1H-pyrazol-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0228]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-pyrimidin-5-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0229]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydrox-6-isopropyl-6-(2-pyrimidin-5-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0230]6-[2-(2-Amino-pyrimidin-5-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0231]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-6-[2-(2-amino-pyrimidin-5-yl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0232]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiazol-4-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0233](S)-4-Hydroxy-6-isopropyl-3-(5-isopropyl-benzothiazol-6-ylsulfanyl)-6-phenethyl-5,6-dihydro-pyran-2-one;

[0234](S)-4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-3-(5-isopropyl-benzothiazol-6-ylsulfanyl)-5,6-dihydro-pyran-2-one;

[0235]3-(2-Amino-7-isopropyl-4-methyl-benzothiazol-6-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0236](S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0237](S)-3-(2-Amino-5-isopropyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0238](R)-3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0239]3-(2-Amino-5-isopropyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(2-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-pyran-2-one;

[0240]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-pyridin-3-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0241]3-(2-tert-Butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(5-hydroxymethyl-thiophen-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0242]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(tetrahydro-furan-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0243]3-(2-tert-Butyl-4-hydroxymethyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0244]3-[2-tert-Butyl-4-(2-hydroxy-ethyl)-5-methyl-phenylsulfanyl]-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0245] 5-Trifluoromethyl-pyridine-2-sulfonic acid{5-tert-butyl-4-[4-hydroxy-6-isopropyl-2-oxo-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-2H-pyran-3-ylsulfanyl]-2-methyl-phenyl}-amide;and

[0246] 5-Trifluoromethyl-pyridine-2-sulfonic acid{5-tert-butyl-4-[4-hydroxy-6-isopropyl-2-oxo-6-(2-pyridin-3-yl-ethyl)-5,6-dihydro-2H-pyran-3-ylsulfanyl]-2-methyl-phenyl}-amide.

[0247] Other preferred compounds are:

[0248]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(3-hydroxymethyl-thiophen-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0249]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(3-methyl-thiophen-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0250]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(2-methyl-thiophen-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0251]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(4-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiophen-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0252]3-(2-Cyclopentyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0253]3-(4-Amino-2-cyclopentyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0254]3-(4-Amino-2-cyclopentyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(4-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0255]3-(6-tert-Butyl-1-hydroxy-indan-5-ylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0256]3-(6-tert-Butyl-1-hydroxy-indan-5-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0257]3-(6-tert-Butyl-1-hydroxy-indan-5-ylsulfanyl)-4-hydroxy-6-[2-(4-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0258]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-furan-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0259]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(3-hydroxymethyl-furan-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0260]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(4-hydroxymethyl-furan-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0261]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(2-methyl-furan-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0262]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(3-methyl-furan-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0263]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-furan-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0264]3-(2-Cyclopentyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-6-(2-furan-3-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0265]3-(6-tert-Butyl-1-hydroxy-indan-5-ylsulfanyl)-6-(2-furan-3-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0266]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(4-hydroxymethyl-thiazol-5-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0267]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiazol-5-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0268]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(5-hydroxymethyl-thiazol-4-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0269]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(5-methyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0270]6-[2-(2-Amino-thiazol-4-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0271]6-[2-(2-Amino-thiazol-5-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0272]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-isothiazol-4-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0273]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-isothiazol-5-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0274]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-isothiazol-3-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0275]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-oxazol-5-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0276]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indol-5-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0277]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indol-5-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0278]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indazol-5-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0279]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indazol-5-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0280]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-6-[2-(1H-benzoimidazol-5-yl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0281]6-[2-(1H-Benzoimidazol-5-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0282]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-6-[2-(3-amino-1H-indazol-5-yl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0283]6-[2-(3-Amino-1H-indazol-5-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0284]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indol-4-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0285]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indol-4-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0286]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indazol-4-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0287]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indazol-4-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0288]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-6-[2-(3-amino-1H-indazol-4-yl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0289]6-[2-(3-Amino-1H-indazol-4-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0290]3-(2-tert-Butyl-6-hydroxymethyl-5-methyl-pyridin-3-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0291]3-(2-tert-Butyl-5-methyl-pyridin-3-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0292]3-(3-tert-Butyl-2-hydroxymethyl-6-methyl-pyridin-4-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0293]3-(5-tert-Butyl-2-methyl-pyridin-4-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0294]3-(4-tert-Butyl-5-hydroxymethyl-thiophen-3-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0295]3-(4-tert-Butyl-thiophen-3-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0296]6-[2-(4-Amino-phenyl)-ethyl]-3-(2-tert-butyl-5-methyl-thiophen-3-ylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0297]3-(2-tert-Butyl-5-methyl-thiophen-3-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0298]6-[2-(4-Amino-phenyl)-ethyl]-3-(4-tert-butyl-5-hydroxymethyl-thiophen-3-ylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0299]6-[2-(4-Amino-phenyl)-ethyl]-3-(3-tert-butyl-4-hydroxymethyl-5-methyl-thiophen-2-ylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0300]3-(3-tert-Butyl-5-methyl-thiophen-2-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one,

[0301]3-(3-tert-Butyl-4-hydroxymethyl-5-methyl-thiophen-2-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0302]3-(3-tert-Butyl-4-hydroxymethyl-5-methyl-thiophen-2-ylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0303]3-(6-tert-Butyl-2,3-dihydro-1H-indol-5-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0304]3-(6-tert-Butyl-2,3-dihydro-1H-indol-5-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0305]3-(6-tert-Butyl-1H-indol-5-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0306]3-(6-tert-Butyl-1H-indol-5-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0307]3-(7-tert-Butyl-1,2,3,4-tetrahydro-quinolin-6-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0308]3-(7-tert-Butyl-1,2,3,4-tetrahydro-quinolin-6-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0309]N-(7-tert-Butyl-6-{6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-4-methyl-benzothiazol-2-yl)-acetamide;

[0310]N-(7-tert-Butyl-6-{4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-4-methyl-benzothiazol-2-yl)-acetamide;

[0311]N-(7-tert-Butyl-6-{6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-4-methyl-benzothiazol-2-yl)-methanesulfonamide;

[0312]N-(7-tert-Butyl-6-{4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-4-methyl-benzothiazol-2-yl)-methanesulfonamide;

[0313]3-(7-tert-Butyl-2-dimethylamino-4-methyl-benzothiazol-6-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0314]3-(7-tert-Butyl-2-dimethylamino-4-methyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0315]3-(7-tert-Butyl-2-hydroxy-4-methyl-benzothiazol-6-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0316]3-(7-tert-Butyl-2-hydroxy-4-methyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0317]3-(2-tert-Butyl-6-hydroxymethyl-5-methyl-pyridin-3-ylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0318]3-(3-tert-Butyl-2-hydroxymethyl-6-methyl-pyridin-4-ylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0319]3-(6-tert-Butyl-2,3-dihydro-1H-indol-5-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0320]3-(6-tert-Butyl-1H-indol-5-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0321]3-(7-tert-Butyl-1,2,3,4-tetrahydro-quinolin-6-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0322]N-{7-tert-Butyl-6-[4-hydroxy-6-isopropyl-2-oxo-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-2H-pyran-3-ylsulfanyl]-4-methyl-benzothiazol-2-yl}-acetamide;

[0323]N-{7-tert-Butyl-6-[4-hydroxy-6-isopropyl-2-oxo-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-2H-pyran-3-ylsulfanyl]-4-methyl-benzothiazol-2-yl}-methanesulfonamide;

[0324]3-(7-tert-Butyl-2-dimethylamino-4-methyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0325]3-(7-tert-Butyl-2-hydroxy-4-methyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0326](S)-3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one:and compounds useful as intermediates in the preparation of the finalproducts are:

[0327] a compound of Formula I A

[0328] wherein

[0329] R₄, R₅, and R₆ are independently H, a straight or branched alkylof 1-6 carbons, a cycloalkyl of 3-6 carbons, (CR′₂)_(n)OR,(CR′₂)_(n)N(R)₂, F, Cl, Br, CN, CF₃, ═O, (CR′₂)_(p)NR′COR,(CR′₂)_(p)SO_(p)R, (CR′₂)_(p)R, (CR′₂)_(p)OCOR, O(CR′₂)_(m)OR,NR(CR′₂)_(m)OR, (CR′₂)_(p)NR′CON(R)₂, (CR′₂)_(p)OCON(R)₂,(CR′₂)_(p)NR′CO₂R, (CR′₂)_(p)C OR, (CR′₂)_(p)CO₂R, (CR′₂)_(p)CON(R)₂,(CR′₂)_(p)NR′SO₂R, (CR′₂)_(p)SO₂N(R)₂, (CR′₂)_(p)NR′SO₂OR,(CR′₂)_(p)OSO₂N(R)₂, (CR′₂)_(p)NR′SO₂N(R)₂, (CR′₂)_(p)C(NR′)N(R)₂,(CR′₂)_(p)NR′C(NR′)N(R)₂, (CR′₂)_(p)Het;

[0330] any two of R₄-R₆ may together form a ring of 5-6 total atomswhich may contain 0-3 heteroatoms;

[0331] n is an integer of from 0 to 3;

[0332] p is an integer from 0 to 2;

[0333] R₇ is a straight or branched alkyl of 1-6 carbons or a carbocycleof 3-6 carbons.

[0334] R is independently H, a straight or branched alkyl of 1-4carbons, (CH₂)_(n)Ph, or a (CH₂)_(n)heterocycle of 5-6 atoms containing1-2 heteroatoms and wherein the (R)₂ in N(R)₂ may form a heterocyclecontaining the nitrogen, all optionally substituted by F, Cl, Br, OR′,CN, CO₂R′, N(R′)₂, NR′COR′, CF₃, or ═O;

[0335] R′ is independently H, a straight or branched alkyl of 1-4carbons, or phenyl;

[0336] R″ is independently H, a straight or branched alkyl of 1-4carbons, F, Cl, Br, OR′, or N(R′)₂;

[0337] Ar₂ is phenyl or Het wherein Het is a heterocycle of from 5-6atoms having from 1-4 heteroatoms.

[0338] Terms useful in describing the instant invention are as follows:

[0339] The term “alkyl” means a straight or branched hydrocarbon radicalhaving from 1 to 12 carbon atoms unless otherwise specified andincludes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl,n-nonyl, n-decyl, undecyl, and dodecyl. The alkyl groups may contain oneor more sites of unsaturation such as double or triple carbon-carbonbonds. The alkyl group is unsubstituted or substituted by from 1 to 3substituents selected from F, Cl, Br, OH, NH₂, CN, NO₂, OCH₃, OCH₂CH₂OH,NHCH₃, or N(CH₃)₂.

[0340] The term “cycloalkyl” means a hydrocarbon ring which containsfrom 3 to 12 carbon atoms unless otherwise specified, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl. Wherepossible, the cycloalkyl group may contain double bonds. The cycloalkylring may be unsubstituted or substituted by from 1 to 3 substituentsselected from alkyl, alkoxy, thioalkoxy all as defined herein, hydroxy,thiol, nitro, halogen, amino, formyl, carboxyl, nitrile, —NH—CO—R,—CO—NHR—, —CO₂R, —COR, aryl, or heteroaryl wherein alkyl (R), aryl, andheteroaryl are defined as herein.

[0341] The term “carbocycle” means cycloalkyl as defined above.

[0342] The term “heteroatoms” means a nitrogen, sulfur, or oxygen.

[0343] The term “heterocycle” means a heterocyclic radical which are 5-6atoms having 1-4 heteroatoms and selected from 1-4 heteroatoms selectedfrom: furan, pyrrole, thiophene, oxazole, isoxazole, thiazole, pyrazole,1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine,pyrimidine, pyrazine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine,piperazine, piperidine, morpholine, thiomorpholine, oxolane, dioxane,sulfolane, unsubstituted or substituted by 1 to 2 substituents selectedfrom alkyl as defined above. For heterocycles containing sulfur, theoxidized sulfur heterocycles containing SO or SO₂ groups are alsoincluded.

[0344] The term “fused heterocycle” refers to a heterocycle that isadjoined as two consecutive positions with a phenyl ring or anotherheterocycle, such rings may include 2-, 3-, 4-, 5-, 6-, 7-, or8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-,5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolinyl, 2-, 3-, 4-,5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl,

[0345] 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6-, or7-benzothiazolyl.

[0346] For purposes of the syntheses of the compounds of the presentinvention, reactive functional groups present in starting materials,reaction intermediates, or reaction products may be protected duringchemical reactions using protecting groups which render the reactivefunctional groups substantially inert to the reaction conditions (seefor example, Protective Groups in Organic Synthesis, 2nd ed., T. W.Green and P. G. Wuts, John Wiley & Sons, New York, N.Y. 1991). Thus, forexample, protecting groups such as the following may be utilized toprotect suitable amino, hydroxyl, and other groups of relatedreactivity: carboxylic acyl groups, such as formyl, acetyl,trifluoroacetyl; alkoxycarbonyl groups, such as ethoxycarbonyl,t-butoxycarbonyl (BOC), β,β,β-trichloroethoxycarbonyl (TCEC),β-iodoethoxycarbonyl; aryloxycarbonyl groups, such as benzyloxycarbonyl,p-methoxybenzyloxycarbonyl, phenoxycarbonyl; trialkyl silyl groups, suchas trimethylsilyl and t-butyldimethylsilyl (TBDMS); and groups such astrityl, tetrahydropyranyl, vinyloxycarbonyl, o-nitrophenylsulfenyl,diphenylphosphinyl, p-toluenesulfonyl, and benzyl may all be utilized.The protecting group may be removed, after completion of the syntheticreaction of interest, by procedures known to those skilled in the art.For example, a BOC group may be removed by acidolysis, a trityl group byhydrogenolysis, TBDMS by treatment with fluoride ions, and TCEC bytreatment with zinc.

[0347] Some of the compounds of Formula I are capable of further formingpharmaceutically acceptable acid-addition and/or base salts. All ofthese forms are within the scope of the present invention.

[0348] Pharmaceutically acceptable acid addition salts of the compoundsof Formula I include salts derived from nontoxic inorganic acids such ashydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic,hydrofluoric, phosphorous, and the like, as well as the salts derivedfrom nontoxic organic acids, such as aliphatic mono- and dicarboxylicacids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids,alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonicacids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate,sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate,dihyrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate,oxalate, malonate, succinates suberate, sebacate, fumarate, maleate,mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate,lactate maleate, tartrate, methanesulfonate, and the like. Alsocontemplated are salts of amino acids such as arginate and the like andgluconate, galacturonate (see, for example, Berge S. M., et al.,“Pharmaceutical Salts,” Journal of Pharmaceutical Science, 1977;66:1-19.

[0349] The acid addition salt of said basic compounds are prepared bycontacting the free base form with a sufficient amount of the desiredacid to produce the salt in the conventional manner.

[0350] Pharmaceutically acceptable base addition salts are formed withmetals or amines, such as alkali and alkaline earth metals or organicamines. Examples of metals used as cations are sodium, potassium,magnesium, calcium, and the like. Examples of suitable amines areN,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine(see, for example, Berge, supra., 1977).

[0351] The base addition salts of said acidic compounds are prepared bycontacting the free acid form with a sufficient amount of the desiredbase to produce the salt in the conventional manner.

[0352] Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

[0353] Certain of the compounds of the present invention possess one ormore chiral centers and each center may exist in the R(D) or S(L)configuration. The present invention includes all enantiomeric andepimeric forms as well as the appropriate mixtures thereof.Configuration drawn is most preferred.

[0354] The compounds of the present invention can be prepared andadministered in a wide variety of oral and parenteral dosage forms.Thus, the compounds of the present invention can be administered byinjection, that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Also, thecompounds of the present invention can be administered by inhalation,for example, intranasally. Additionally, the compounds of the presentinvention can be administered transdermally. It will be obvious to thoseskilled in the art that the following dosage forms may comprise as theactive component, either a compound of Formula I or a correspondingpharmaceutically acceptable salt of a compound of Formula 1.

[0355] For preparing pharmaceutical compositions from the compounds ofthe present invention, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier can be one or more substances which may alsoact as diluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

[0356] In powders, the carrier is a finely divided solid which is in amixture with the finely divided active component.

[0357] In tablets, the active component is mixed with the carrier havingthe necessary binding properties in suitable proportions and compactedin the shape and size desired.

[0358] The powders and tablets preferably contain from five or ten toabout seventy percent of the active compound. Suitable carriers aremagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

[0359] For preparing suppositories, a low melting wax, such as a mixtureof fatty acid glycerides or cocoa butter, is first melted, and theactive component is dispersed homogeneously therein, as by stirring. Themolten homogenous mixture is then poured into convenient sized molds,allowed to cool, and thereby to solidify.

[0360] Liquid form preparations include solutions, suspensions, andemulsions, for example, water or water propylene glycol solutions. Forparenteral injection, liquid preparations can be formulated in solutionin aqueous polyethylene glycol solution.

[0361] Aqueous solutions suitable for oral use can be prepared bydissolving the active component in water and adding suitable colorants,flavors, stabilizing and thickening agents as desired.

[0362] Aqueous suspensions suitable for oral use can be made bydispersing the finely divided active component in water with viscousmaterial, such as natural or, synthetic gums, resins, methylcellulose,sodium carboxymethylcellulose, and other well-known suspending agents.

[0363] Also included are solid form preparations which are intended tobe converted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

[0364] The pharmaceutical preparation is preferably in unit dosage form.In such form the preparation is divided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

[0365] The quantity of active component in a unit dose preparation maybe varied or adjusted from 0.1 mg to 100 mg preferably 0.5 mg to 100 mgaccording to the particular application and the potency of the activecomponent. The composition can, if desired, also contain othercompatible therapeutic agents.

[0366] In therapeutic use as antagonists of a retroviral protease, asagents for the treatment of infections caused by a retrovirus includingHIV, or as agents for the treatment of diseases due to AIDS, thecompounds utilized in the pharmaceutical method of this invention areadministered at the initial dosage of about 0.01 mg to about 100 mg/kgdaily. A daily dose range of about 0.01 mg to about 10 mg/kg ispreferred. The dosages, however, may be varied depending upon therequirements of the patient, the severity of the condition beingtreated, the compound being employed. Determination of the proper dosagefor a particular situation is within the skill of the art. Generally,treatment is initiated with smaller dosages which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under the circumstances isreached. For convenience, the total daily dosage may be divided andadministered in portions during the day, if desired.

[0367] The compounds of the instant invention, protease inhibitors, canbe used as a component of initial patient antiretroviral therapy for HIVas, for example, in the following regimen:

[0368] Choose one combination of nucleoside reverse transcriptaseinhibitors

[0369] Zidovudine+lamivudine

[0370] Zidovudine+didanosine

[0371] Zidovudine+zalcitabine

[0372] Didanosine+stavudine

[0373] Didanosine+lamivudine

[0374] Stavudine+lamivudine

[0375] Abacavir+zidovudine+lamivudine

[0376] AND one of the compounds of the instant invention.

[0377] In addition, one may use one of the nucleoside reversetranscriptase inhibitor combinations above with one of the agents belowplus a compound of the instant invention.

[0378] Nelfinavir

[0379] Indinavir

[0380] Saquinavir (soft gel-cap now preferred over hard gel-cap)

[0381] Ritonavir

[0382] Nevirapine

[0383] Delavirdine

[0384] Efavirenz

[0385] The compounds of the instant invention can be used in multiplecombinations with available antiretroviral drugs for combinationtherapy. The following are illustrative: Drug class/agents DosageNucleoside reverse transcriptase inhibitors Abacavir 300 mg bidDidanosine 200 mg bid (for patients <60 kg, 125 mg bid) Lamivudine 150mg bid (for patients <50 kg, 2 mg/kg bid) Stavudine 40 mg bid (forpatients <60 kg, 30 mg/kg bid) Zalcitabine 0.75 mg tid Zidovudine 300 mgbid Non-nucleoside reverse transcriptase inhibitors Delavirdine 400 mgtid Efavirenz 600 mg qd Nevirapine 200 mg bid Protease inhibitorsIndinavir 800 mg q8 h Nelfinavir 750 mg tid Ritonavir 600 mg bidSaquinavir 600 mg tid (hard gel-cap formulation), 1200 mg tid (softgel-cap formulation)

[0386] The compounds of the instant invention can be used with orinstead of the following for the treatment of established HIV infection.Preferred Strong evidence of clinical benefit and/or sustainedsuppression of plasma viral load. One choice each from column A andcolumn B. Drugs are listed in random, not priority, order: Column AColumn B Indinavir (AI) ZDV + ddl (AI) Nelfinavir (AII) d4T + ddl (AII)Ritonavir (AI) ZDV + ddC (AI) Saquinavir − SGC (AII) ZDV + 3TC (AI)Ritonavir + Saquinavir SGC or HGC d4T + 3TC (AII) (BII) Efavirenz (AII)Alternative Less likely to provide sustained virus suppression, or datainadequate. Nevirapine or delavirdine + two NRTIs (Column B, above)(BII)

[0387] The compounds of the instant invention can be used with thefollowing drugs available through treatment investigational new drugprotocols. Amprenavir Adefovir Abacavir (Agenerase; Drug (Preveon)(1592-U89) 141W94) Source Gilead Glaxo-Wellcome Vertex; 800-GILEAD-5800-501-4672 Glaxo-Wellcome 800-248-9757 Class Nucleotide RT NucleosideRT Protease Inhibitor Inhibitor Inhibitor Usual 60 mg po qd or 300 mg pobid 1200 mg po bid dose 120 mg po qd + L-carnitine 500 mg po qd SideProximal renal tubular Hypersensitivity: Nausea, diarrhea, effectsdysfunction, nausea, 2-5% usually in rash, headache (major) elevatedLFTs first 4 weeks (fever, nausea, vomiting, morbilliform rash)

[0388] The compounds of the present invention can be prepared accordingto the various synthetic schemes that follow. Protecting groups may beused when appropriate throughout many of the schemes. Althoughspecifically noted in certain schemes, the appropriate use and choice ofprotecting groups is well-known by one skilled in the art, and is notlimited to the specific examples below. It is also understood that suchgroups not only serve to protect chemically reactive sites, but also toenhance solubility or otherwise change physical properties. A goodgeneral reference for protecting group preparation and deprotection is“Protecting Groups in Organic Synthesis” by Theodora Green. A number ofgeneral reactions such as oxidations and reductions are not shown indetail but can be done by methods understood by one skilled in the art.General transformations are well-reviewed in “Comprehensive OrganicTransformation” by Richard Larock, and the series “Compendium of OrganicSynthetic Methods” published by Wiley-Interscience. In general, thestarting materials were obtained from commercial sources unlessotherwise indicated.

[0389] There are three major components of the synthesis of the desiredproducts: the formation of a ketone precursor; the cyclization of thatketone into the dihydropyrone ring system; and the addition of the thiolcomponent to complete the preparation of the compounds of the invention.Schemes 1 through 6 address the various methods for preparation ofketones indicated as C, D, G, and K.

[0390] Aldehyde Synthesis

[0391] The desired aldehydes which can be used in Schemes 2 and 3 areprepared by a number of methods as indicated in Scheme 1. Theappropriate ester can be reduced to the corresponding alcohols and thenoxidized to the aldehyde. Another method involves preparation of ananion with an appropriate base and trapping with a reagent, such as DMF,to prepare the aldehyde.

[0392] The desired ketones can be prepared as shown in Schemes 2 and 3.The appropriate alpha halo ketone can be displaced with triphenylarsineto prepare an arsenate reagent. In a similar manner, triphenylphosphinecan be used to prepare a Wittig reagent which will also carry out thereaction shown in Scheme 2. Upon treating the arsenate reagent and thealdehyde with base such as potassium carbonate, the chalcone derivativeC is formed. Compound C can then be reduced using hydrogen with anappropriate catalyst to prepare ketone D.

[0393] Alternatively, the desired enones C can be prepared by reactionof the appropriate methylketones and aldehydes using Ba(OH)₂ in EtOH asdescribed in Synthesis, 1983:502-504, An. Quim, Ser. C,1981;77(2):222-294, and Pol. J. Chem., 1982;56(10-112):1435. In asimilar fashion, the enones C can also be prepared by reaction of theappropriate methylketones and aldehydes using NaOH in EtOH as describedby Kohler and Chadwell, Org. Synth. Coll., 1941;1:78. The relative ratioof aldehyde, ketone, base, and temperature (RT to reflux) variedaccording to the substitution pattern of the aldehyde and ketone. Therehave also been reports of conversion of A and B to chalcones C underacidic conditions using H₂SO₄ and acetic anhydride. This may beaccomplished by direct treatment with acid or the acid may be used todehydrate the aldol intermediate if it does not dehydrate during thereaction with base.

[0394] The resulting chalcones C were converted into ketones D byreduction as noted previously in Scheme 2. The reduction was generallyaccomplished by hydrogenation using palladium on barium sulfate at roomtemperature in tetrahydrofuran. On occasion, overreduction to thealcohol was observed. The isolated alcohol or the crude mixture can beoxidized to the ketone with Jones reagent.

[0395] The reduction of the enone to the corresponding ketone can becarried out via a number of alternative methods including but notlimited to: metals in ammonia as described in Org. Reactions,1976;23:1-253; ethylene glycol and RuCl₂[P(Ph)₃]₃ as described inSynthesis, 1973:359: and copper hydride reagents as described in J.Amer. Chem. Soc., 1974;96:3686.

[0396] Preparation of the ketone G can be accomplished from anappropriate acid(E) and appropriate nucleophile using the Weinrebmethodology described in Tetrahedron Letters, 1987:1857. The appropriateacid can be converted to the acid chloride by treatment with neatthionyl chloride or by treatment with oxalyl chloride in methylenechloride with a catalytic amount of DMF. Treatment of the acid chloridewith N,O-dimethylhydroxylamine with bases such as pyridine ortriethylamine in inert solvents such as methylene chloride from 0° C. toreflux will give intermediate F. Intermediate F can then be converted toG by treatment with the appropriate nucleophile, such as Grignardreagents, at 0° C. to reflux in solvents such as tetrahydrofuran orether. An alternative method of converting the acid E to ketone G is bytreatment with alkyl lithiums at −78° C. to reflux as described in J.Med. Chem., 1996;39:2659 and J. Amer. Chem., Soc. 1970;92:2590. Anotherroute is treatment of the acid chloride with nucleophiles(organomagnesium, copper, cadmium, or zinc reagents) as reviewed in Org.React., 1954;8:28 and Tetrahedron Lett., 1970:4647.

[0397] An alternative preparation of ketone D can be accomplished byreaction of an allylic alcohol I with an appropriate halide H usingpalladium acetate as described in Tetrahedron, 1979;35:329 andTetrahedron Lett., 1991;32:2121.

[0398] There are a number of catalysts and conditions which will effectthis transformation such as: Pd(OAc)₉, NaHCO₃, DMF, tetrabutylammoniumchloride at room temperature to reflux; Pd(OAc)₉, triethylamine,acetonitrile at room temperature to reflux. The desired ketone D canalso be prepared by acid catalyzed reaction of allylic alcohol 1, or anenone, with an appropriate heterocycles as described in Heterocycles,1987;25:399.

[0399] An alternate preparation of ketone G can be accomplished byreaction of aldehyde A with an appropriate nucleophile such as an organolithium or Grignard reagents from −78° C. to room temperature in inertsolvents to afford the alcohol. The desired ketone G can by formed byoxidation of the resulting alcohol with Jones reagent or other oxidizingconditions such as the Swern oxidation which are well-known to oneskilled in the art.

[0400] Acid E can be converted to desired ketone K utilizing a four steproute indicated in Scheme 7. The appropriate acid E can be convertedinto the corresponding β-ketoester J utilizing conditions described inTetrahedron Letters, 1992:1945 and Angew. Chem. Int. Ed. 1979:72. Theresulting β-ketoester L can be treated with a base, such as NaH orlithium diisopropylamide (LDA), then with an appropriate alkylatingagent, R′X at 0° C. to room temperature to give the alkylatedβ-ketoester. The β-ketoester can be decarboxylated with acid intetrahydrofuran at reflux. Alternatively the β-ketoester can behydrolyzed with base to the acid, then heated with or without acid togive the desired ketone K.

[0401] The ketones C, D, G, and K and those prepared from Scheme 7 arecyclized to the dihydropyrone ring following the routes shown in Schemes8 and 9. Scheme 9 also describes methods for obtaining optically pureforms of the dihydropyrone ring which is a recognized and importantaspect of the current invention. The same methods can be used to produceracemic compounds if the resolution step is removed.

[0402] The dihydropyrone ring system can be prepared as described inCan. J. Chem., 1974;52:2157-2164 and Synthetic Communications, 1988;18(9):949-963. Reaction of the dianion of acetoacetate (L) with theappropriate ketone (C, D, G, or K) in inert solvents such astetrahydrofuran at 0° C. to room temperature gave aldol intermediate M.H₂O can be added directly to the reaction to effect closure.Alternatively the reaction can be worked up by addition of acetic acidor ammonium chloride and the aldol product isolated and characterized ortaken on crude. The aldol product M can be closed by treating withdilute sodium hydroxide with or without tetrahydrofuran present. Thetetrahydrofuran may be necessary to assist in solubilizing the aldolintermediate M. Protecting groups on intermediate M can be removedbefore closure to assist in solubilizing the intermediate in base.

[0403] Other routes are available to form the dihydropyrone ring such asthose described in: J. C. S. Chem. Comm., 1979:578; J. Am. Chem. Soc.,1984; 106:4294; and J. Org. Chem., 1975;40:1610.

[0404] The dihydropyrone ring system can also be prepared opticallyenriched as shown in Scheme 9. The appropriate ketone (C, D, G, or K)can be reacted with the appropriate Reformatsky reagent or theequivalent lanthamide species (Tetrahedron, 1981;37(Supp. 1):175; J.Org. Chem., 1984;49:3904) in inert solvents such as tetrahydrofuran at−78° C. to reflux to afford the aldol intermediate. The two antipodescan be separated by a chiral HPLC column such as Chiralcel OD (90%hexane:0.1% TFA:10% isopropyl alcohol) or selective enzymatic hydrolysiswith enzymes such as Candida antarctica “B” lipase in phosphate bufferwith co-solvents such as isopropyl alcohol at room temperature. Theresolved ester can be hydrolyzed to the acid O* using base understandard conditions.

[0405] Intermediate R* can also be prepared in a chiral form by reactionof ketone C, D, G or K with a chiral ester Q to give an intermediatewhich is a mixture of diastereomers (J. Org. Chem., 1982;47:91;Tetrahedron, 1980;36:227). The aldol mixture can be separated byrecrystallization or by chromatography to give each enantiomer.Hydrolysis of the ester using base affords acid R*.

[0406] Intermediate O can be prepared in racemic form and then resolvedby classical means such as co-crystallization with a chiral amine suchas 1-(1-naphthyl)ethylamine in solvents such as H₂O. Analysis of thechiral salt by x-ray may allow the determination of the absolutestereochemistry of intermediate O*.

[0407] The intermediates O* or R* can be converted to P* by activationof the acid and treatment with the magnesium salt of a half acid ester.Then P*, like M, may be converted to N or N* by base.

[0408] Schemes 10 to 14 describe the synthesis of a number of the tosylreagents (X, BB, HH) which are used to introduce the 3-thiol moiety tothe dihydropyrones of the invention.

[0409] Phenol S can be reacted with electrophiles, such as HC(OEt)₃ ininert solvents with a Lewis acid, to give the para-substituted phenol.The phenol can be protected with groups such as methoxyethoxymethyl ortertbutyldimethylsilyl which are known to one skilled in the art. Thederivatized phenol can be converted to the corresponding thiol using avariety of methods (Tetrahedron Lett., 1996:4523; Chem. Lett., 1985:1307and Tetrahedron Lett., 1993 :393). The Newman-Kwart rearrangement isalso useful for the conversion of phenol to thiophenol as described inJ. Org. Chem., 1966:3980; Synth., 1975:43; and J. Chem. Eng. Data,1975;20:443. Phenol U can be treated with bases such as sodium hydrideand dimethylthiocarbamoyl chloride in solvents such as DMF ortetrahydrofuran at 0° C. to reflux to give V. Vigorous heating of V attemperatures in the 200° C. to 330° C. range affords intermediate X. Thefree thiol can be prepared by reduction of derivatives such as W withdiisobutylaluminum hydride (DIBAL-H) or sodium borohydride in inertsolvents such as toluene or tetrahydrofuran from −78° C. to roomtemperature or by hydrolysis in base. The desired thiotosylate X can beprepared by reaction of the thiol with tosyl bromide and base such astriethylamine or pyridine in inert solvents such as carbon tetrachlorideat 0° C. to room temperature.

[0410] Another route into desired thiotosyl reagents is indicated inScheme 11. Aniline Y can be converted to the corresponding phenol usinga variety of conditions (J. Org. Chem., 1951;16:586; Org. Synth.,1955;Coll. Vol. 3:130). The phenol can be treated with sodiumthiocyanate, sodium bromide, and bromine in MeOH at 0° C. to 50° C. toincorporate the thiocyanate to give Z (Synth., 1992:656). The phenol canbe modified or protected using conditions which are understood by oneskilled in the art. The thiocyanate can be converted to the thiol (AA)by treatment with dithiothreitol (DTT) in phosphate buffer in ethanol atroom temperature to reflux or by treatment with lithium aluminum hydride(LAH) in inert solvents such as tetrahydrofuran at 0° C. to roomtemperature. The desired thiotosylate BB can be prepared by reaction ofthe thiol with tosyl bromide and base as described in Scheme 10.

[0411] Thiol AA can be converted to the disulfide (CC) by treatment withiodine and triethylamine in EtOAc. The disulfide can act as a protectinggroup for the sulfur. Various reactions can then be carried out on CCand the disulfide converted back to the thiol by treatment withdithiothreitol (DTT) using similar conditions as described in Scheme 11.Reaction of the free thiophenol with tosyl bromide as previouslydescribed affords the desired tosyl reagent BB.

[0412] Thiocyanate Z can be converted to the thiol and then tothiotosylate DD using conditions which have been described in previousschemes. Thiotosylate DD can be derivatized or a protecting groupattached using conditions known to one skilled in the art to give BB.

[0413] The nitro aromatic EE (J. Org. Chem., 1951:586) can be reduced tothe corresponding aniline by hydrogenation over Raney Nickel at roomtemperature. The thiocyanate can be introduced para to the amine in asimilar manner as described in Scheme 11. Aniline FF can be converted toGG by modification of the amine, conversion to thiol, and tosylation aspreviously described. Alternatively aniline II can be protected,converted to the thiol, and reacted with tosyl bromide to give JJ.Aniline JJ can be deprotected and then modified to give HH. Thereactions in this scheme have been previously described or are known toone skilled in the art.

[0414] Scheme 15 shows the convergent preparation of the desiredcompounds of the invention. The dihydropyrones (N) described in Schemes8 and 9 are reacted with the tosyl reagents (X, BB, HH) described inSchemes 10 to 14 to produce the target compounds.

[0415] The desired dihydropyrone KK can be prepared by reaction with theappropriate dihydropyrone N or N*, thiotosylate (X, BB, HH), andpotassium carbonate in dimethylformamide (DMF) at room temperature.Other bases and solvents will also effect this reaction such astriethylamine in ethanol or sodium hydride in tetrahydrofuran at 0° C.to reflux. Alternatively, the intermediate N can be brominated with NBSin tert-butanol and then displaced with the thiols such as AA and GG.Scheme 16 describes alternative methods for effecting the separation ofenantiomers into optically pure forms after formation of thedihydropyrone ring.

[0416] It has been shown that tetrahydropyrones can be resolved asdescribed in the ICI patent WO 93/06235. The 4-hydroxydihydropyrone canbe converted to a ester and the ester hydrolyzed with an enzyme toafford chiral material. This or other similar enzymatic processes may beapplicable to the dihydropyrones as indicated in Scheme 16. The4-hydroxydihydropyrone may also be resolved by classical means byconversion into a salt with chiral amines such as1-(1-naphthyl)ethylamine. The salt may be recrystallized and then freedto afford the desired chiral material MM*.

[0417] Scheme 17 shows the general preparation of a number ofsubstituted heterocycles. When X is a halogen, a metal halogen exchangecan be preformed to prepare the appropriate anion which can be trappedwith an appropriate electrophile (E). This can be used to prepareheterocyclic aldehydes by trapping with DMF, thiols by trapping withsulfur, and alkyl groups by trapping with alkyl ketones or alkylhalides. In certain cases an appropriate base will deprotonate aheterocyclic hydrogen to prepare an anion directly. The followingreferences exemplify Scheme 17: J. Chem. Soc., Perkin Trans. 1,1997:3465; J. Chem. Soc., Perkin Trans. 1, 1995:2913; J. Org. Chem.,1971;36(18):2690.

[0418] Preparation of Aldehydes

EXAMPLE A-1

[0419] 5-Methyl-thiazole-4-carbaldehyde

[0420] A solution of 2.48 g (14.4 mmol) of5-methyl-thiazole-4-carboxylic acid ethyl ester (J. Chem. Soc., PerkinTrans. 1, 1982:159-164) in dichloromethane (CH₂Cl₂) (50 mL) was cooledto −78° C. under nitrogen. DIBAL (Diisobutylaluminum hydride) (1.0 M inCH₂Cl₂, 15 mmol) was added dropwise, and the solution was stirred at lowtemperature for 45 minutes. Another 10 mmol of DIBAL was then addeddropwise, and the mixture was stirred for another 45 minutes. A solutionof methanol (MeOH):acetic acid (10 mL:5 mL) was added slowly, followedby H₂O. The organic layer was separated, washed with brine, and dried(MgSO₄). Concentration gave a residue which was chromatographed onsilica gel, eluting with 2:1 hexane:ethyl acetate (EtOAc), to give thetitle compound.

[0421]¹H NMR (CDCl₃): δ 2.76 (s, 3H), 8.58 (s, 1H), 10.14 (s, 1H).

EXAMPLE A-2

[0422] 2-Methyl-thiazole-4-carbaldehyde

[0423] A mixture of 5.52 g (30 mmol) of 4-chloromethyl-2-methylthiazolehydrochloride and 0.5 M NaOH (180 mL) was refluxed for 8 hours and thenstirred for 18 hours at room temperature. EtOAc and H₂O were added. Theorganic phase was separated, washed with brine, and dried (MgSO₄).Concentration gave 4-(hydroxymethyl)-2-methylthiazole.

[0424]¹H NMR (CDCl₃): δ 2.63 (s, 3H), 4.66 (s, 2H), 6.96 (s, 1H).

[0425] The crude product (2.2 g, 17 mmol) was oxidized with MnO₂ (20 g)in 75 mL of CHCl₃ for 16 hours. The suspension was filtered, and thefiltrate was concentrated. The residue was chromatographed on silicagel, eluting with 2:1 hexane:EtOAc, to give the title compound.

[0426]¹H NMR (CDCl₃): δ 2.71 (s, 3H), 7.98 (s, 1H), 9.89 (s, 1H).

EXAMPLE A-3

[0427] 2-iso-Propyl-thiazole-4-carbaldehyde

[0428] A solution of 2.7 g (13 mmol) of2-isopropyl-thiazole-4-carboxylic acid ethyl ester (J. Med. Chem.,1998:602-617) in CH₂Cl₂ (50 mL) was cooled to −78° C. under nitrogen andtreated dropwise with DIBAL (15 mL of 1.0 M in CH₂Cl₂; 15 mmol). Themixture was stirred at low temperature for 45 minutes and then treatedwith another 15 mL of DIBAL. The solution was stirred for 1 hour at −78°C. Five percent citric acid was added, and the mixture was extractedwith EtOAc (3×100 mL). The combined extracts were washed with brine,dried (MgSO₄), and concentrated. Chromatography of the residue oversilica gel, eluting with 3:1 hexane:EtOAc, gave the title compound.

[0429]¹H NMR (CDCl₃): δ 1.37 (d, 6H), 3.30-3.35 (m, 1H), 8.01 (s, 1H),9.93 (s, 1H).

EXAMPLE A-4

[0430] 4-iso-Propyl-thiazole-5-carbaldehyde

[0431] A solution of 5.9 g (30 mmol) of4-isopropyl-thiazole-5-carboxylic acid ethyl ester (J. Chem. Soc.,Perkin Trans. 1, 1982:159-164) in toluene (100 mL) was cooled in an icebath under nitrogen and treated dropwise with DIBAL (150 mL of 1.0 M;150 mmol). The mixture was stirred at low temperature for 45 minutes andthen allowed to warm to room temperature overnight. H₂O was addedcautiously, and the mixture was extracted with EtOAc (3×200 mL). Thecombined extracts were washed with brine, dried (MgSO₄), andconcentrated. The crude 5-(hydroxymethyl)-4-isopropyl-thiazole thusobtained was used as is in the next step.

[0432]¹H NMR (CDCl₃): δ 1.30 (d, 6H), 3.13-3.20 (m, 1H), 4.85 (s, 2H),8.67 (s, 1H).

[0433] A mixture of 4.65 g (30 mmol) of crude5-(hydroxymethyl)-4-isopropyl-thiazole in 200 mL of chloroform (CHCl₃)was treated with 45 g of MnO2 and stirred at room temperature for 2.5hours. The suspension was filtered, and the filtrate was concentrated.The residue was chromatographed on silica gel, eluting with 3:1hexane:EtOAc, to give the title compound.

[0434]¹H NMR (CDCl₃): δ 1.40 (d, 6H), 3.62-3.69 (m, 1H), 8.97 (s, 1H).10.17 (s, 1H).

EXAMPLE A-5

[0435] 5-iso-Propyl-thiazole-4-carbaldehyde

[0436] A solution of 6.8 g (37 mmol) of5-isopropyl-thiazole-4-carboxylic acid methyl ester (J. Chem. Soc.,Perkin Trans. 1, 1982:159-164) in CH₂Cl₂ (120 mL) was cooled to −78° C.under nitrogen and treated dropwise with DIBAL (37 mL of 1.0 M inCH₂Cl₂; 37 mmol). The mixture was stirred at low temperature for 45minutes and then treated with another 20 mL of DIBAL. The solution wasstirred for 1 hour at −78° C. H₂O was added, and the mixture wasextracted with EtOAc (3×150 mL). The combined extracts were washed withbrine, dried (MgSO₄), and concentrated. Chromatography of the residueover silica gel, eluting with 2:1 hexane:EtOAc, gave the title compound.

[0437]¹H NMR (CDCl₃): δ 1.34 (d, 6H), 4.09-4.16 (m, 1H), 8.63 (s, 1H),10.20 (s, 1H).

EXAMPLE A-6

[0438] 4-iso-Propyl-thiazole-2-carbaldehyde

[0439] A solution of 2.1 g (11 mmol) of4-isopropyl-thiazole-2-carboxylic acid ethyl ester (J. Med. Chem.,1998:602-617) in CH₂Cl₂ (50 mL) was cooled to −78° C. under nitrogen andtreated dropwise with DIBAL (12 mL of 1.0 M in CH₂Cl₂; 12 mmol). Themixture was stirred at low temperature for 1 hour and then treated withanother 7 mL of DIBAL. The solution was stirred for 30 minutes at −78°C. H₂O was added, and the mixture was extracted with EtOAc (3×100 mL).The combined extracts were washed with brine, dried (MgSO₄), andconcentrated. Chromatography of the residue over silica gel, elutingwith 3:1 hexane:EtOAc, gave the title compound.

[0440]¹H NMR (CDCl₃): δ 1.35 (d, 6H), 3.16-3.23 (m, 1H), 7.33 (s, 1H),9.96 (s, 1H).

[0441] The remaining aldehydes were either commercially available orknown in the chemical literature, as sumrnarized in Table A below. TABLEA Preparation of Aldehydes Example Aryl Method of Preparation ¹H NMRData A-7

Commercially available A-8

Synthesis, 1987:998-1001 (CDCl₃): δ 8.22(s, 1H), 8.88(s, 1H), 10.10(s,1H). A-9

Synthesis, 1987:998-1001 (CDCl₃): δ 8.51(s, 1H), 9.10(s, 1H), 10.10(s,1H). A-10

Acta. Chemica Scandinavica, 1966:20:2649-2657 (CDCl₃): δ 2.49(s, 3H),7.29(s, 1H), 9.86(s, 1H). A-11

Acta. Chemica Scandinavica, 1966,20:2649-2657 (CDCl₃): δ 2.51(s, 3H),7.71(s, 1H), 9.80(s, 1H). A-12

J. Amer. Chem. Soc., 1982:4934-4943 (CDCl₃): δ 2.76(s, 3H), 8.94(s, 1H),10.11(s, 1H). A-13

Bull. Chim. France, 1967:2235-2238 (CDCl₃): δ 2.19(s, 3H), 7.74(s, 1H),9.77(s, 1H), 11.69 (brs, 1H). A-14

Commercially available A-15

Commercially available A-16

Commercially available A-17

Commercially available A-18

J. Org. Chem., 1990;55(26):6317-6328 (CDCl₃): δ 6.69(m, 1H), 6.85(m,1H), 7.46(m, 1H), 9.2(br s, 1H), 9.82 (s, 1H). A-19

Commercially available A-20

Commercially available A-21

Commercially available A-22

Commercially available A-23

Commercially available A-24

Commercially available A-25

Commercially available A-26

Commercially available A-27

Commercially available A-28

Commercially available A-29

Commercially available A-30

Chem Pharm. Bull., 1986;34(10):4116-4125 (CDCl₃): δ 6.67(m, 1 H),7.25(m, 1H), 7.45(d, 1H), 7.74(d, 1H), 8.15(s, 1H), 8.70(brs, 1H), 10.00(s, 1H). A-31

J.O.C., 1987;53:107-109 A-32

Commercially available A-33

Commercially available A-34

Commercially available A-35

Commercially available

[0442] Methods for the Preparation of Enones: General Method 1.Preparation of Enones via Triphenylarsonium Salts

[0443] A mixture of the appropriate aldehyde from Examples A-1 to A-29(1.0 equiv.), the crude arsonate salt (usually(3-methyl-2-oxobutyl)triphenylarsonium bromide, prepared in Synthesis,1988:975-977; 1.1 equiv.), potassium carbonate (1.1 equiv.), and 1% H₂Oin CH₃CN was stirred for 1 to 18 hours at room temperature. The solidswere filtered, and the filtrate was chromatographed on silica gel toremove the arsenate by-products.

EXAMPLE B-1

[0444] 4-Methyl-1-(4-methyl-thiazol-5-yl)-pent-1-en-3-one

[0445] The title compound was prepared as described in General Method 1using 1.4 g (11.0 mmol) of 4-methyl-5-thiazolecarbaldehyde (ExampleA-12), 6.2 g (13.1 mmol) of (3-methyl-2-oxobutyl)triphenylarsoniumbromide, 1.8 g (13.1 mmol) of potassium carbonate, 75 mL ofacetonitrile, and 0.75 mL of H₂O. Chromatography of the residue, elutingwith 3:1 hexane:EtOAc gave the title compound.

[0446]¹H NMR (CDCl₃): δ 1.13 (d, 6H), 2.54 (s, 3H), 2.75-2.82 (m 1H),6.50 (d, 1H), 7.73 (d, 1H), 8.66 (s, 1H).

[0447] General Method 2. Preparation of Enones via Condensation withBa(OH)₂

[0448] The desired enones were prepared by reaction of the appropriatemethylketones and aldehydes by the methods described in Synthesis,1983:502-504; An. Quim, Ser. C, 198 1;77(2):222-224; Org. Synth. Coll.,1941;I:78; and Pol. J. Chem., 1982;56(10-112): 1435. To a reaction flaskwas added aldehyde (1-2 equiv.), ketone (1-2 equiv.), 95% EtOH, andanhydrous or hydrated Ba(OH)₂ (23 mg/mmol). The reaction was stirred atroom temperature or heated at reflux for up to 2 days. The reaction wascooled to room temperature. The EtOH was evaporated, and the crudereaction was partitioned between EtOAc and 1N HCl. The aqueous layer wasextracted with EtOAc. The combined organic extracts were dried (MgSO₄)and concentrated. The crude product was purified by flash chromatographyor recrystallization.

Example B-2

[0449] 1-Furan-2-yl-4-methyl-pent-1-en-3-one

[0450] The titled compound was prepared according to General Method 2 byreacting 2-furaldehyde (117 mmol), 2-methyl-butan-3-one (117 mmol),anhydrous Ba(OH)₂ (2.2 g) and EtOH (200 mL) to afford the desirecompound.

[0451]¹H NMR (CDCl₃): δ 1.18 (d, 6H), 2.83 (m, 1H), 6.46 (m, 1H), 6.65(m, 1H), 6.73 (d, 1H), 7.38 (d, 1H), 7.50 (m, 1H).

[0452] The following enones were prepared using either General Method 1(the arsonate salt) or General Method 2 (the Ba(OH)₂ method) from thecorresponding aldehydes in Examples A-1 to A-35: TABLE B Preparation ofEnones

NMR Data (δ for vinyl protons. Solvent: CDCl₃) Example R₇ General Methodof Mass Spec B-3

Gen. Method 1 7.05, 7.64 B-4

Gen. Method 1 7.14, 7.53 B-5

Gen. Method 1 6.58, 7.72 B-6

Gen. Method 1 6.90, 7.52 B-7

Gen. Method 1 7.01, 7.57 B-8

Gen. Method 1 7.06, 7.43 B-9

Gen. Method 1 7.12, 7.54 B-10

Gen. Method 1 7.11, 7.49 B-11

Gen. Method 1 6.52, 7.78 B-12

Gen. Method 1 7.24, 7.64 B-13

Gen. Method 1 6.95, 7.60 B-14

Gen. Method 1 6.93, 7.41 B-15

Gen. Method 1 7.33, 7.60 B-16

Gen. Method 1 6.96, 7.51 B-17

Gen. Method 1 MS (APCI): 243 (M + H) B-18

Gen. Method 1 MS (APCI): 243 (M + H) B-19

Gen. Method 1 MS (APCI): 243 (M + H) B-20

Gen. Method 1 MS (APCI): 261 (M + H) B-21

Gen. Method 1 MS (APCI): 261 (M + H) B-22

Gen. Method 1 MS (APCI): 200 (M + H) B-23

Gen. Method 2 6.74, 7.86 B-24

Gen. Method 2 6.90, 7.73 B-25

Gen. Method 2 6.74, 7.57 B-26

Gen. Method 2 6.80, 7.56 B-27

Gen. Method 2 B-28

Gen. Method 1 MS (APCI): 164 (M + H) B-29

Gen. Method 1 MS (APCI): 165 (M + H) B-30

Gen. Method 2 6.59, 7.56 B-31

Gen. Method 1 6.82, 7.78 B-32

Gen. Method 1 6.78, 6.99 B-33

Gen. Method 2 7.11, 7.70 B-34

Gen. Method 2 6.79, 7.49 B-35

Gen. Method 2 6.84, 7.66 B-36

Gen. Method 2 6.73, 7.43

[0453] Names corresponding to the enones in Table B above are:

[0454] B-3: 4-Methyl-1-thiazol-2-yl-pent-1-en-3-one;

[0455] B-4: 4-Methyl-1-thiazol-4-yl-pent-1-en-3-one;

[0456] B-5: 4-Methyl-1-thiazol-5-yl-pent-1-en-3-one;

[0457] B-6: 4-Methyl-1-(5-methyl-thiazol-2-yl)-pent-1-en-3-one;

[0458] B-7: 4-Methyl-1-(4-methyl-thiazol-2-yl)-pent-1-en-3-one;

[0459] B-8: 4-Methyl-1-(2-methyl-thiazol-4-yl)-pent-1-en-3-one;

[0460] B-9: 4-Methyl-1-(5-methyl-thiazol-4-yl)-pent-1-en-3-one;

[0461] B-10: 1-(2-Isopropyl-thiazol-4-yl)-4-methyl-pent-1-en-3-one;

[0462] B-11: 1-(4-Isopropyl-thiazol-5-yl)-4-methyl-pent-1-en-3-one;

[0463] B-12: 1-(5-Isopropyl-thiazol-4-yl)-4-methyl-pent-1-en-3-one;

[0464] B-13: 1-(4-Isopropyl-thiazol-2-yl)-4-methyl-pent-1-en-3-one;

[0465] B-14: N-[4-(4-Methyl-3-oxo-pent-1-enyl)-thiazol-2-yl]-acetamide;

[0466] B-15: 4-Methyl-1-pyridin-2-yl-pent-1-en-3-one;

[0467] B-16: 4-Methyl-1-pyridin-4-yl-pent-1-en-3-one;

[0468] B-17: 4-Methyl-1-(2-trifluoromethyl-phenyl)-pent-1-en-3-one;

[0469] B-18: 4-Methyl-1-(3-trifluoromethyl-phenyl)-pent-1-en-3-one;

[0470] B-19: 4-Methyl-1-(4-trifluoromethyl-phenyl)-pent-1-en-3-one;

[0471] B-20:4-Methyl-1-(3-fluoro-5-trifluoromethyl-phenyl)-pent-1-en-3-one;

[0472] B-21:4-Methyl-1-(4-fluoro-3-trifluoromethyl-phenyl)-pent-1-en-3-one;

[0473] B-22: 4-(4-Methyl-3-oxo-pent-1-enyl)-benzonitrile;

[0474] B-23: 4-Methyl-1-(3-fluoro-2-methyl-phenyl)-pent-1-en-3-one;

[0475] B-24: 4-Methyl-1-(2-fluoro-phenyl)-pent-1-en-3-one;

[0476] B-25: 4-Methyl-1-(4-fluoro-phenyl)-pent-1-en-3-one;

[0477] B-26: 4-Methyl-1-(3-fluoro-phenyl)-pent-1-en-3-one;

[0478] B-27: 4-Methyl-1-(3,4-difluoro-phenyl)-pent-1-en-3-one;

[0479] B-28: 4-Methyl-1-(1H-pyrrol-3-yl)-pent-1-en-3-one;

[0480] B-29: 1-(1H-Imidazol-4-yl)-4-methyl-pent-1-en-3-one;

[0481] B-30: 4-Methyl-1-thiophen-3-yl-pent-1-en-3-one;

[0482] B-31: 1-(1H-Indol-5-yl)-4-methyl-pent-1-en-3-one;

[0483] B-32: 4-Methyl-1-(2-methyl-thiophen-3-yl)-pent-1-en-3-one;

[0484] B-33: 4-Methyl-1-(2,6-difluoro-phenyl)-pent-1-en-3-one;

[0485] B-34: 4-Methyl-1-(3,5-difluoro-phenyl)-pent-1-en-3-one;

[0486] B-35: 4-Methyl-1-(2,4-difluoro-phenyl)-pent-1-en-3-one; and

[0487] B-36: 4-Methyl-1-(3,4,5-trifluoro-phenyl)-pent-1-en-3-one.

[0488] Methods for the Preparation of Requisite Ketones: General Method3. Preparation of Ketones by Hydrogenation of Enones

[0489] The substituted arylpropiophenones were prepared by hydrogenationof the corresponding enones at room temperature at 50 psi intetrahydrofuran (THF) utilizing a number of catalysts such as: 5%palladium (Pd) on barium sulfate (BaSO₄) or (Ph₃P)₃RhCl or 10% Pd oncarbon or 5% Pd on CaCO₃. The catalyst was filtered off and theresulting ketone recrystallized or purified by flash chromatography.

EXAMPLE C-1

[0490] 4-Methyl-1-pyridin-4-yl-pentan-3-one

[0491] The title compound was prepared according to General Method 3using 4-methyl-1-pyridin-4-yl-pent-1-en-3-one (Example B-16; 1.81 g),(Ph₃P)₃RhCl (0.5 g), and THF (100 mL) at 50 psi. The title compound wasflash chromatographed using 98:2 CH₂Cl₂:MeOH as eluent. ¹H NMR (CDCl₃):δ 1.15 (d, 6H), 2.5-2.7 (m, 1H), 2.7-2.8 (m, 2H), 2.85-2.95 (m, 2H), 7.1(d, 2H), 8.5(d, 2H).

EXAMPLE C-2

[0492] 4-Methyl-1-(4-methyl-thiazol-5-yl)-pentan-3-one

[0493] The title compound was prepared as described in General Method 3using 1.73 g (8.86 mmol) of4-methyl-1-(4-methyl-thiazol-5-yl)-pent-1-en-3-one (prepared in ExampleB-1) and 0.4 g of 5% Pd/BaSO₄ in THF:MeOH (25 mL:25 mL). The crudeproduct was chromatographed on silica gel, eluting with 2:1hexane:EtOAc, to give the title compound. ¹H NMR (CDCl₃): δ 1.03 (d,6H), 2.35 (s, 3H), 2.49-2.56 (m, 1H), 2.72 (t, 2H), 2.98 (t, 2H), 8.49(s, 1H).

[0494] Synthesis of Appropriate Halogenated Heterocycles Necessary forKetone Synthesis (General Methods 4a and 4b)

Example Starting Material-1 (SM)

[0495] (5-Bromo-thiophen-2-yl)-methanol

[0496] The title compound was prepared by reduction of5-bromo-2-thiophenecarbaldehyde (137 mmol) with sodium borohydride (137mmol) in MeOH (500 mL). The reaction was stirred for 2 hours at 0° C.and 2 hours at room temperature. The MeOH was evaporated, and saturatedammonium chloride was added followed by 2N HCl. The aqueous layers wereextracted with EtOAc, dried (MgSO4), and concentrated. Flashchromatography over silica gel using 100% CH₂Cl₂ as eluent afforded thetitle compound. ¹H NMR (CDCl₃): δ 4.74 (d, 2H), 6.75 (m, 1H), 6.91 (d,1H).

Example Starting Material-2

[0497] (4-Bromo-thiophen-2-yl)-methanol

[0498] The title compound was prepared in a similar manner to ExampleSM-1 by reduction of 4-bromo-2-thiophenecarboxaldehyde (122 mmol) withsodium borohydride (12 mmol) in MeOH (500 mL).

[0499]¹H NMR (CDCl₃): δ 4.80 (d, 2H), 6.93 (d, 1H), 7.18 (d, 1H).

Example Starting Material-3

[0500] (3-Bromo-thiophen-2-yl)-methanol

[0501] The title compound was prepared by reduction of3-bromothiophene-2-carboxylic acid methyl ester (45 mmol) with lithiumaluminum hydride (45 mmol) in THF (150 mL) at 0° C. for 1 hour and thenovernight at room temperature. The reaction was worked up by addition of1 mL of H₂O, 1 mL of 15% NaOH, and 3 mL of H₂O followed by filtrationthrough celite. Concentration of the filtrate gave the title compound. IH NMR (CDCl₃): δ 4.80 (s, 2H), 6.96 (d, 1H), 7.26 (d, 1H).

Example Starting Material-4

[0502] 1-Trityl-4-iodopyrazole

[0503] The title compound was prepared by combining 4-iodopyrazole (10g, 52 mmol), triphenylmethyl chloride (14.4 g, 51.6 mmol), triethylamine(NEt₃) (7.2 mL, 52 mmol), and DMF (80 mL). After stirring overnight, themixture was poured onto ice water. The precipitated solid was collectedand recrystallized to give the title compound as a solid, mp 193-194° C.

[0504]¹H NMR (CDCl₃): δ 7.11 (m, 6H), 7.32 (m, 9H), 7.41 (s, 1H), 7.67(s, 1H).

Example Starting Material-5 (SM)

[0505] (4-Bromo-thiophen-3-yl)-methanol

[0506] The title compound was prepared in a similar manner to ExampleSM-1 by reduction of 4-bromo-3-thiophenecarbaldehyde (Bull. Soc. Chim.France, 1967;11:4115) with sodium borohydride in MeOH. ¹H NMR (CDCl₃): δ2.05 (s, 2H), 7.27-7.34 (m, 2H).

Example Starting Material-6 (SM)

[0507] (2-Bromo-thiophen-3-yl)-methanol

[0508] A solution of 10.0 g (39.0 mmol) of2-bromo-3-bromomethyl-thiophene (J. Chem. Soc. Perkin Trans. II,1983:813) in 130 mL of acetone was treated with a solution of 11.4 g(67.1 mmol) of AgNO₃ in 110 mL of H₂O. The mixture was stirred at roomtemperature for 1 hour and filtered. The solid was washed with Et₂O andacetone; the combined filtrate and washings were concentrated. Theresidue was extracted with CH₂Cl₂, and the organic layer was dried(MgSO₄) and concentrated. The crude product was chromatographed oversilica gel, eluting with hexane:EtOAc:CH₂Cl₂ (80:5:15 to 60:30:10) togive the title compound.

[0509]¹H NMR (CDCl₃) δ 1.67 (t, 1H), 4.63 (d, 2H), 7.03 (d, 1H), 7.26(d, 1H).

Example Starting Material-7 (SM)

[0510] 3-Bromo-4-ethyl-fluorobenzene

[0511] 2-Bromo-4-fluoroacetophenone (10.0 g, 46.1 mmol) in THF (120 mL)was treated with BF₃—OEt₂ (22.9 g, 20.4 mL, 161 mmol) and followed byNaBH₃CN (7.24 g, 155 mmol) added portionwise. The resulting mixture washeated to reflux under N₂ overnight and then cooled to room temperature.Diethyl ether (Et₂O) was added; the organic layer was washed withsaturated NaHCO₃/H₂O and brine, dried (MgSO₄), filtered, andconcentrated. The resulting residue was subjected to flash silica gelchromatography, eluting with 4:1 (hexanes:EtOAc) to afford theintermediate alcohol. ¹H NMR (CDCl₃): δ 1.46 (d, 3H), 1.98 (bs, 1H),5.21 (q, 1H), 7.03-7.10 (m, 1H), 7.26 (dd, 1H), 7.58 (dd, 1H).

[0512] The alcohol isolated above (4.0 g, 18 mmol) was dissolved inhexanes (20 mL) and treated with trimethylsilyl chloride (11.9 g, 13.9mL, 109 mmol), NaI (16.4 g, 109 mmol), and CH₃CN (5.7 mL, 109 mmol). Theresulting slurry was stirred at room temperature under N₂ overnight.Et₂O was added followed by H₂O. The phases were separated, and theaqueous phase was extracted again with Et₂O; the combined organic phaseswere washed with sodium bisulfite (NaHSO₃)/H₂O and brine, dried (MgSO₄),filtered, and concentrated. The resulting residue was subjected to flashsilica gel chromatography, eluting with hexanes to afford the titlecompound. ¹H NMR (CDCl₃): δ 1.20 (t, 3H), 2.72 (q, 2H), 6.93-6.99 (m,1H), 7.18 (dd, 1H), 7.27 (dd, 1H).

Example Starting Material-8 (SM)

[0513] (2-Bromo-5-fluoro-phenyl)-methanol

[0514] 2-Bromo-5-fluorobenzylbromide (2.0 g, 7.46 mmol) was dissolved indioxane (25 mL) and H₂O (25 mL), and CaCO₃ (3.84 g, 38.39 mmol) wasadded. The mixture was heated to reflux overnight. The solution wasconcentrated, and the residue was partitioned between H₂O and CH₂Cl₂.The organic phase was washed with 1N HCl and brine, dried (MgSO₄),filtered, and concentrated to afford the title compound. ¹H NMR (CDCl₃):δ 2.00 (t, 1H), 4.72 (d, 2H), 6.85-6.92 (m, 1H), 7.26 (dd, 1H), 7.48(dd, 1H).

[0515] The remaining halides were commercially available, as summarizedin Table C below. TABLE C Aryl Halides Example Aryl SM-9

SM-10

SM-11

SM-12

SM-13

SM-14

SM-15

SM-16

SM-17

SM-18

SM-19

[0516] Methods for the Preparation of Requisite Ketones: General Method4a and 4b. Preparation of Ketones via Pd-Catalyzed Coupling

[0517] General Method 4a is the method described in Tetrahedron,1979;35:329 and Tetrahedron Letters, 1991;32:2121. The appropriate arylhalide (Br or I; 1 equiv.), allylic alcohol (1-2 equiv.), tetrabutylammonium chloride (1 equiv.), sodium bicarbonate (2-3 equiv.), DMF(0.1-1 mL per mmol of halide), and palladium acetate (0.01-0.1 equiv.)were added to a reaction vessel. The solution was heated to 40° C. to100° C. for 1 to 24 hours. On occasion, pyrrolidine (0.2-1 equiv.) wasalso added. The reaction was cooled to room temperature and partitionedbetween H₂O and CH₂Cl₂. The solution was filtered through celite and theaqueous layer extracted two times with CH₂Cl₂. The organic extracts werewashed with brine and then dried (MgSO₄). Purification was usuallycarried out by flash chromatography.

[0518] General Method 4b is the method described in Tetrahedron,1979;35:329-340 with slight modifications. The appropriate aryl halide(Br or I; 1 equiv.), allylic alcohol (1-2 equiv.), sodium iodide(0.01-0.050 equiv.), sodium bicarbonate (1-3 equiv.), triphenylphosphine (0.01-0.050 equiv.), DMF (0.1-1 mL per mmol of halide), andpalladium acetate (0.01-0.1 equiv.) were added to a reaction vessel. Thesolution was heated to 40° C. to 100° C. for 1 to 24 hours. Pyrrolidine(0.2-1 equiv.) was also added at times. The reaction was cooled to roomtemperature and partitioned between H₂O and CH₉Cl₂. The solution wasfiltered through celite and the aqueous layer extracted two times withCH₂Cl₂. The organic extracts were washed with brine and then dried(MgSO₄). Purification was usually carried out by flash chromatography.

EXAMPLE C-3

[0519] 4-Methyl-1-pyridin-3-yl-pentan-3-one

[0520] The title compound was prepared according to General Method 4ausing 3-iodo-pyridine (36.6 mmol), 4-methyl-1-penten-3-ol (54.9 mmol),tetrabutyl ammonium chloride (36.6 mmol), sodium bicarbonate (91.5mmol), pyrrolidine (˜1.5 mL), DMF (15 mL), and palladium acetate (0.51g). The title compound was flash chromatographed eluting withEtOAc:CH₂Cl₂:hexane 50:25:25.

[0521]¹NMR (CDCl₃): δ 1.15 (d, 6H), 2.5-2.7 (m, 1H). 2.7-2.9 (m. 2H),2.85-2.95 (m. 2H), 7.2-7.3 (m, 1H), 7.5-7.6 (m, 1H), 8.4-8.5 (m, 2H).

EXAMPLE C-4

[0522] 1-Furan-3-yl-4-methyl-pentan-3-one

[0523] The title compound was prepared according to General Method 4ausing 3-bromofuran (17 mmol), 4-methyl-1-penten-3-ol (25.5 mmol),tetrabutyl ammonium chloride (17 mmol), sodium bicarbonate (42.5 mmol),DMF (15 mL), and palladium acetate (0.9 mmol). The title compound wasflash chromatographed eluting with EtOAc:hexane (5:95 to 10:90).

[0524]¹NMR (CDCl₃): δ 1.05 (d, 6H), 2.5-2.7 (m, 1H), 2.65 (s, 4H), 6.2(s, 1H), 7.25 (m, 1H), 7.3 (m, 1H).

EXAMPLE C-5

[0525] 4-Methyl-1-thiophen-3-yl-pentan-3-one

[0526] The title compound was prepared according to General Method 4busing 3-bromothiophene (20 mmol), 4-methyl-1-penten-3-ol (30 mmol),sodium iodide (0.7 mmol), sodium bicarbonate (24 mmol),triphenylphosphine (0.6 mmol), DMF (15 mL), and palladium acetate (0.2mmol). The title compound was flash chromatographed using EtOAc:hexane(5:95 to 10:90).

[0527]¹NMR (CDCl₃): δ 1.05 (d, 6H), 2.5-2.7 (m, 1H), 2.7-2.8 (t, 2H),2.85-2.95 (t, 2H), 6.90-9.95 (m, 2H), 7.2-7.3 (m, 1H).

[0528] Alternatively, the title compound could be prepared byhydrogenation (General Method 3) of the enone prepared in Example B-30.

[0529] General Method 5. Preparation of Silylated Intermediates.

[0530] The appropriate alcohol (1 equiv.), and imidazole (1.2 equiv.)were added to a reaction vessel followed by CH₂Cl₂ or THF (7-10 mL permmol of alcohol), t-Butyldimethylsilyl chloride (1.1 equiv.) was addedand the reaction stirred at room temperature (3 hours to 4 days). Thereaction was filtered, washed with H₂O and brine, dried (MgSO₄), andconcentrated. The product was either flashed chromatographed or carriedon crude.

EXAMPLE C-6

[0531]1-[5-(tert-Butyl-dimethyl-silanyloxymethyl)-thiophen-2-yl]-4-methyl-pentan-3-one

[0532] The title compound was prepared according to General Method 5using 1-(5-hydroxymethyl-thiophen-2-yl)-4-methyl-pentan-3-one (seeExample C-24 below; 73.0 mmol), t-butyldimethylsilyl chloride (80.3mmol), imidazole (80.3 mmol) and CH₂Cl₂ (300 mL). ¹H NMR (CDCl₃): δ 0.09(s, 6H), 0.92 (s, 9H), 1.09 (d, 6H), 2.59 (m, 1H), 2.81 (t, 2H), 3.06(t, 2H), 4.78 (s, 2H), 6.61 (d, 1H), 6.69 (d, 1H).

[0533] The following ketones were prepared as indicated [either fromreduction of the corresponding enones from Examples B-1 to B-36 (GeneralMethod 3) OR from the corresponding halides from Examples SM-1 to SM-19(General Method 4a or 4b)]. In some cases, the following ketones werealso prepared from silylation of an existing ketone using General Method5: TABLE D Preparation of Ketones

General Analytical Data Example R₈ Method (¹H NMR or MS) C-7 

Gen. Method 3 (CDCl₃): δ 1.06(d, 6H), 2.56-2.63(m, 1H), 2.97(t, 2H),3.24(t, 2H), 7.13(d, 1H), 7.60(d, 1H) C-8 

Gen. Method 3 (CDCl₃): δ 1.04(d, 6H), 2.53-2.60(m, 1H), 2.87(m, 2H),3.08(m, 2H), 6.96(m, 1H), 8.70(m, 1H) C-9 

Gen. Method 3 (CDCl₃): δ 1.08(d, 6H), 2.55-2.61(m, 1H), 2.78(t, 2H),3.15(t, 2H), 7.60(s, 1H), 8.63(s, 1H) C-10

Gen. Method 3 (CDCl₃): δ 1.03(d, 6H), 2.33(s, 3H), 2.52-2.59(m, 1H),2.88-2.92(m, 2H), 3.09-3.13(m, 2H), 7.18(s, 1H) C-11

Gen. Method 3 (CDCl₃): δ 1.05(d, 6H), 2.34(s, 3H), 2.55-2.62(m, 1H),2.93(t, 2H), 3.18(t, 2H), 6.65(s, 1H) C-12

Gen. Method 3 (CDCl₃): δ 1.02(d, 6H), 2.50-2.56(m, 1H), 2.62(s, 3H),2.80-2.84(m, 2H), 2.91-2.94(m, 2H), 6.68(s, 1H) C-13

Gen. Method 3 (CDCl₃): δ 1.00(d, 6H), 2.35(s, 3H), 2.50-2.57(m, 1H),2.86(s, 4H), 8.45(s, 1H) C-14

Gen. Method 3 (CDCl₃): δ 1.02(d, 6H), 1.32(d, 6H), 2.52-2.58(m, 1H),2.83(t, 2H), 2.95(t, 2H), 3.20-3.27(m, 1H), 6.70(s, 1H) C-15

Gen. Method 3 (CDCl₃): δ 1.07(d, 6H), 1.26(d, 6H), 2.53-2.60(m, 1H),2.75(t, 2H), 3.04(t, 2H), 3.07-3.14(m, 1H), 8.56(s, 1H) C-16

Gen. Method 3 (CDCl₃): δ 1.07(d, 6H), 1.27(d, 6H), 2.56-2.63(m, 1H),2.89-2.97(m, 4H), 3.28-3.35(m, 1H), 8.53(s, 1H) C-17

Gen. Method 3 (CDCl₃): δ 1.10(d, 6H), 1.26(d, 6H), 2.60-2.65(m, 1H),2.98(t, 2H), 2.99-3.05(m, 1H), 3.24(t, 2H), 6.68(s, 1H) C-18

Gen. Method 3 (CDCl₃): δ 1.04(d, 6H), 2.20(s, 3H), 2.52-2.59(m, 1H),2.76-2.80(m, 2H), 2.86-2.90(m, 2H), 6.51(s, 1H) C-19

Gen. Method 3 (CDCl₃): δ 1.15(d, 6H), 2.5-2.7(m, 1H), 2.9-3.0(m, 2H),3.0-3.1(m, 2H), 7.05-7.15(m, 1H), 7.2(d, 1H), 7.5-7.6(dt, 1H), 8.5(d,1H) C-20

Gen. Method 3 (CDCl₃): δ 1.15(d, 6H), 2.5-2.7(m, 1H), 2.7-2.9(m, 2H),2.85-2.95(m, 2H), 5.95(m, 1H), 6.25(m, 1H), 7.3(m, 1H) C-21

Gen. Method 3 (complete reduction of C-20) MS(APCI): 171(M + H) C-22

Gen. Method 4b (CDCl₃): δ 1.1(d, 6H), 2.5-2.7(m, 1H), 2.8-2.9(t, 2H),3.05-3.15(t, 2H), 6.75-6.80(m, 1H), 6.85-6.95(m, 1H), 7.05-7.15(m, 1H)C-23

Gen. Method 4b (CDCl₃): δ 1.1(d, 6H), 2.5-2.7(m, 1H), 2.7-2.8(m, 2H),2.8-2.9(m, 2H), 4.75(s, 2H), 6.85(s, 1H), 6.9(s, 1H) C-24

Gen. Method 4b (CDCl₃): δ 1.1(d, 6H), 2.5-2.7(m, 1H), 2.8-2.9(t, 2H),3.05-3.15(t, 2H) 4.75(s, 2H), 6.65(d, 1H), 6.8(d, 1H) C-25

Gen. Method 4b (CDCl₃): δ 1.0(d, 6H), 2.4-2.5(m, 1H), 2.7-2.8(m, 2H),2.8-2.9(m, 2H), 4.7(s, 2H), 6.75(d, 1H), 7.1(d, 1H) C-26

Gen. Method 5 (from C-25) (CDCl₃): δ 0.00(s, 6H), 0.82(s, 9H), 0.95(d,6H), 2.44(m, 1H), 2.62(t, 2H), 2.72(t, 2H), 4.70(s, 2H), 6.70(d, 1H),7.01(d, 1H) C-27

Gen. Method 5 (from C-23) (CDCl₃): δ 0.09(s, 6H), 0.85(s, 9H), 0.92(d,6H), 2.58(m, 1H), 2.73(m, 2H), 2.82(m, 2H), 4.81(s, 2H), 6.74(s, 1H),6.82(s, 1H) C-28

Gen. Method 3 (CDCl₃): δ 1.08(d, 6H), 2.21(d, 3H), 2.53-2.62(m, 1H),2.70(t, 2H), 2.89(t, 2H), 6.84-6.92(m, 2H), 7.03-7.10(m, 1H) C-29

Gen. Method 3 C-30

Gen. Method 3 (CDCl₃): δ 1.05(d, 6H), 2.50-2.60(m, 1H), 2.71-2.76(m,2H), 2.83-2.89(m, 2H), 6.95(m, 2H), 7.13(m, 2H) C-31

Gen. Method 4a ¹HNMR(CDCl₃): δ 1.04(d, 6H), 2.55(sp, 1H), 2.64-2.74(m,4H), 7.11-7.17(m, 7H), 7.26-7.35(m, 9H), 7.48(s, 1H) C-32

Gen. Method 3 MS(APCI): 166(M + H) C-33

Gen. Method 3 MS(APCI): 167(M + H) C-34

Gen. Method 4a MS(APCI): 179(M + H) C-35

Gen. Method 4a MS(APCI): 194(M + H) C-36

Gen. Method 3 MS(APCI): 200(M − H) C-37 Ph Prepared as reported in Bull.Soc. Chim. Fr., 1956: 1653. C-38

Gen. Method 4 MS(APCI): 206(M) C-39

Gen. Method 5 (from C-38) MS(APCI): 319(M − H) C-40

Gen. Method 3 ¹HNMR(CDCl₃): δ 1.09(d, 6H), 2.56-2.63(m, 1H), 2.84(t,2H), 3.01(t, 2H), 6.49(m, 1H), 7.03-7.06(m, 1H), 7.17(m, 1H),7.29-7.33(m, 1H), 7.46(s, 1H), 8.23(s, 1H) C-41

Gen. Method 4b (CDCl₃): δ 1.03(d, 6H), 2.51-2.58(m, 1H), 2.81-2.87(m,4H), 4.60(s, 2H), 6.90(d, 1H), 7.17(d, 1H) C-42

Gen. Method 5 (from ABOVE) (CDCl₃): δ 0.0(s, 6H), 0.83(s, 9H), 0.99(d,6H), 2.50(m, 1H), 2.71(m, 4H), 4.56(s, 2H), 6.81(d, 1H), 7.06(s, 1H)C-43

Gen. Method 4b (CDCl₃): δ 1.09(d, 6H), 2.19(s, 3H), 2.60(m, 1H),2.75-2.80(m, 4H), 6.85-6.90(m, 2H) C-44

Gen. Method 4b (CDCl₃): δ 1.04-1.06(d, 6H), 2.13(s, 3H), 2.51-2.58(m,1H), 2.72-2.75(t, 2H), 2.94-2.98(t, 2H), 6.72-6.75(d, 1H), 6.97-6.98(d,1H) C-45

Gen. Method 3 (CDCl₃): δ 1.06(d, 6H), 2.37(s, 3H), 2.52-2.59(m, 1H),2.67-2.71(t, 2H), 2.77-2.81(t, 2H), 6.78-6.79(d, 1H), 6.98-7.00(d, 1H)C-46

Gen. Method 4a (CDCl₃): δ 1.05(d, 6H), 2.50-2.61(m, 1H), 2.88(t, 2H),3.12(t, 2H), 4.62(d, 2H), 6.96(d, 1H), 7.08(d, 1H) C-47

Gen. Method 5 (from C-46) (CDCl₃): δ 0.08(s, 6H), 0.91(s, 9H), 1.08(d,6H), 2.50-2.70(m, 1H), 2.78-2.81(t, 2H), 3.03-3.08(t, 2H), 4.63(s, 2H),6.94(d, 1H), 7.03(d, 1H) C-48

Gen. Method 3 (CDCl₃): δ 1.09(d, 6H), 2.52-2.66(m, 1H), 2.71-2.76(m,2H), 2.90-2.95(m, 2H), 6.79-6.89(m, 2H), 7.09-7.19(m, 1H) C-49

Gen. Method 3 (CDCl₃): δ 1.07(d, 6H), 2.50-2.64(m, 1H), 2.73-2.78(m,2H), 2.84-2.90(m, 2H), 6.59-6.67(m, 2H), 7.69-7.72(m, 1H) C-50

Gen. Method 3 (CDCl₃): δ 1.06(d, 6H), 2.51-2.60(m, 1H), 2.71-2.77(m,2H), 2.84-2.89(m, 2H), 6.72-6.81(m, 2H), 7.12-7.20(m, 1H) C-51

Gen. Method 3 (CDCl₃): δ 1.07(d, 6H), 2.49-2.61(m, 1H), 2.71-2.76(m,2H), 2.80-2.85(m, 2H), 6.74-6.84(m, 2H) C-52

Gen. Method 4a C-53

Gen. Method 4a (CDCl₃): δ 1.10(d, 6H), 1.19(t, 3H), 2.54-2.64(m, 3H),2.69-2.77(m, 2H), 2.82-2.90(m, 2H), 6.80-6.87(m, 2H), 7.08-7.13(m, 1H)C-54

Gen. Method 4a (CDCl₃): δ 1.04(d, 6H), 2.37(bs, 1H), 2.50-2.66(m, 1H),2.77-2.82(m, 2H), 2.84-2.94(m, 2H), 4.70(s, 2H), 6.88-6.91(m, 1H),7.08-13(m, 2H) C-55

Gen. Method 5 (from C-54) C-56

Gen. Method 4a

EXAMPLE C-57

[0534]2,2,2-Trifluoro-N-[4-(4-methyl-3-oxo-pentyl)-thiazol-2-yl]-acetamide

[0535] A solution of C-18 (from Table D above; 1.21 g, 5.03 mmol) in 6NHCl (50 mL) and THF (5 mL) was refluxed for 4 hours and then cooled toroom temperature. Solid NaHCO₃ was added portionwise with caution untilpH 7.2 was achieved. The suspension was extracted with EtOAc. Thecombined extracts were washed with brine, dried (MgSO₄), andconcentrated. The residue was chromatographed over silica gel, elutingwith EtOAc, to give the deprotected compound. ¹H NMR (CDCl₃): δ 1.04 (d,6H), 2.52-2.59 (m, 1H), 2.75 (m, 4H), 6.06 (s, 1H).

[0536] A solution of the ketone prepared above (0.75 g, 3.8 mmol) inCH₂Cl₂ (50 mL) was cooled in an ice bath, treated with NEt₃ (0.6 mL, 4.3mmol) and trifluoromethyl acetic anhydride (0.6 mL, 4.3 mmol), andallowed to warm to room temperature. H₂O was added. The organic layerwas separated, washed with brine, and dried (MgSO₄). Concentration gavean oil which was chromatographed over silica gel, eluting with EtOAc, togive the title compound. I H NMR (CDCl₃): δ 1.10 (d, 6H), 2.58-2.65 (m,1H), 2.83-2.86 (m, 2H), 2.91-2.95 (m, 2H), 6.61 (s, 1H).

[0537] Names corresponding to the ketones from Table D above are:

[0538] C-7: 4-Methyl-1-thiazol-2-yl-pentan-3-one;

[0539] C-8: 4-Methyl-1-thiazol-4-yl-pentan-3-one;

[0540] C-9: 4-Methyl-1-thiazol-5-yl-pentan-3-one;

[0541] C-10: 4-Methyl-1-(5-methyl-thiazol-2-yl)-pentan-3-one;

[0542] C-11: 4-Methyl-1-(4-methyl-thiazol-2-yl)-pentan-3-one;

[0543] C-12: 4-Methyl-1-(2-methyl-thiazol-4-yl)-pentan-3-one;

[0544] C-13: 4-Methyl-1-(5-methyl-thiazol-4-yl)-pentan-3-one;

[0545] C-14: 1-(2-Isopropyl-thiazol-4-yl)-4-methyl-pentan-3-one;

[0546] C-15: 1-(4-Isopropyl-thiazol-5-yl)-4-methyl-pentan-3-one;

[0547] C-16: 1-(5-Isopropyl-thiazol-4-yl)-4-methyl-pentan-3-one;

[0548] C-17: 1-(4-Isopropyl-thiazol-2-yl)-4-methyl-pentan-3-one;

[0549] C-18: N-[4-(4-Methyl-3-oxo-pentyl)-thiazol-2-yl]-acetamide;

[0550] C-19: 4-Methyl-1-pyridin-2-yl-pentan-3-one;

[0551] C-20: 1-Furan-2-yl-4-methyl-pentan-3-one;

[0552] C-21: 4-Methyl-1-(tetrahydro-furan-2-yl)-pentan-3-one;

[0553] C-22: 4-Methyl-1-thiophen-2-yl-pentan-3-one;

[0554] C-23: 1-(5-Hydroxymethyl-thiophen-3-yl)-4-methyl-pentan-3-one;

[0555] C-24: 1-(5-Hydroxymethyl-thiophen-2-yl)-4-methyl-pentan-3-one;

[0556] C-25: 1-(2-Hydroxymethyl-thiophen-3-yl)-4-methyl-pentan-3-one;

[0557] C-26:1-[2-(tert-Butyl-dimethyl-silanyloxymethyl)-thiophen-3-yl]-4-methyl-pentan-3-one;

[0558] C-27:1-[5-(tert-Butyl-dimethyl-silanyloxymethyl)-thiophen-3-yl]-4-methyl-pentan-3-one;

[0559] C-28: 1-(3-Fluoro-2-methyl-phenyl)-4-methyl-pentan-3-one;

[0560] C-29: 1-(2-Fluoro-phenyl)-4-methyl-pentan-3-one;

[0561] C-30: 1-(4-Fluoro-phenyl)-4-methyl-pentan-3-one;

[0562] C-31: 4-Methyl-1-(1-trityl-1H-pyrazol-3-yl)-pentan-3-one;

[0563] C-32: 4-Methyl-1-(1H-pyrrol-3-yl)-pentan-3-one;

[0564] C-33: 1-(1H-Imidazol-4-yl)-4-methyl-pentan-3-one;

[0565] C-34: 4-Methyl-1-(pyrimidin-5-yl)-pentan-3-one;

[0566] C-35: 1-(2-Amino-pyrimidin-5-yl)-4-methyl-pentan-3-one;

[0567] C-36: 4-(4-Methyl-3-oxo-pentyl)-benzonitrile;

[0568] C-37: 4-Methyl-1-phenyl-pentan-3-one;

[0569] C-38: 1-(2-Hydroxymethyl-phenyl)-4-methyl-pentan-3-one;

[0570] C-39:1-[2-(tert-Butyl-dimethyl-silanyloxymethyl)-phenyl]-4-methyl-pentan-3-one.

[0571] C-40: 1-(1H-Indol-5-yl)-4-methyl-pentan-3-one;

[0572] C-41: 1-(4-Hydroxymethyl-thiophen-3-yl)-4-methyl-pentan-3-one;

[0573] C-42:1-[4-(tert-Butyl-dimethyl-silanyloxymethyl)-thiophen-3-yl]-4-methyl-pentan-3-one;

[0574] C-43: 4-Methyl-1-(4-methyl-thiophen-3-yl)-pentan-3-one;

[0575] C-44: 4-Methyl-1-(3-methyl-thiophen-2-yl)-pentan-3-one;

[0576] C-45: 4-Methyl-1-(2-methyl-thiophen-3-yl)-pentan-3-one;

[0577] C-46: 1-(3-Hydroxymethyl-thiophen-2-yl)-4-methyl-pentan-3-one;

[0578] C-47:1-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-thiophen-2-yl]-4-methyl-pentan-3-one;

[0579] C-48: 1-(2,6-Difluoro-phenyl)-4-methyl-pentan-3-one;

[0580] C-49: 1-(3,5-Difluoro-phenyl)-4-methyl-pentan-3-one;

[0581] C-50: 1-(2,4-Difluoro-phenyl)-4-methyl-pentan-3-one;

[0582] C-51: 1-(3,4,5-Trifluoro-phenyl)-4-methyl-pentan-3-one;

[0583] C-52: 1-(5-Fluoro-2-methyl-phenyl)-4-methyl-pentan-3-one;

[0584] C-53: 1-(2-Ethyl-5-fluoro-phenyl)-4-methyl-pentan-3-one;

[0585] C-54: 1-(4-Fluoro-2-hydroxymethyl-phenyl)-4-methyl-pentan-3-one;

[0586] C-55:1-[2-(tert-Butyl-dimethyl-silanyloxymethyl)-4-fluoro-phenyl]-4-methyl-pentan-3-one;and

[0587] C-56: 1-(4-Fluoro-2-methyl-phenyl)-4-methyl-pentan-3-one.

[0588] General Method 6. Preparation of β-Ketoesters

[0589] Methyl acetoacetate was added dropwise to a slurry of hexanewashed sodium hydride in anhydrous THF at 0° C. and the reaction stirredat 0° C. (15 minutes to 3 hours). N-Butyl lithium (nBuLi) was then addedat 0° C. and the reaction stirred at 0° C. (15 minutes to 24 hours). Asolution of the requisite ketone in THF was added, and the reactionmixture was stirred at 0° C. to room temperature for 15 minutes to 24hours. To the reaction mixture was added acetic acid [or dilute HCl orsaturated ammonium chloride (NH₄Cl)] with stirring, and the THF wasremoved on a rotoevaporator. The viscous reaction mixture waspartitioned between H₂O and EtOAc. After separation of the layers, theaqueous layer was again extracted with EtOAc. The combined organicextracts were dried (MgSO₄) and concentrated. The aldol intermediateswere either purified by flash chromatography or taken on crude.

[0590] General Method 7. Desilylation of Silyl Ether Protecting Groups

[0591] The appropriate silanyloxy compound (1 equiv.) was added to areaction vessel followed by THF (3-5 mL per mmol of silanyloxycompound). This solution was treated with tetrabutylammonium fluoride(1.2-2.0 equiv.) and stirred at room temperature (1 hour to 1 day). Theproduct was partitioned between EtOAc and 1N HCl. The organic layer wasdried (MgSO₄) and concentrated. The product was either flashedchromatographed or carried on crude.

EXAMPLE D-1

[0592]5-Hydroxy-6-methyl-5-[2-(4-methyl-thiazol-5-yl)-ethyl]-3-oxo-heptanoicAcid Methyl Ester

[0593] The title compound was prepared as described in General Method 6from 1.00 g (8.61 mmol) of methyl acetoacetate, 0.38 g (9.50 mmol) ofsodium hydride, 4.5 mL of 2.1 M nBuLi (9.45 mmol), and 1.53 g (7.75mmol) of 4-methyl-1-(4-methyl-thiazol-5-yl)-pentan-3-one (prepared inExample C-2.) The crude compound was used without purification in thenext step.

[0594] The following compounds were prepared in similar fashion from theappropriate ketone (from Examples C-1 to C-57) and were used withoutpurification. TABLE E Preparation of β-Ketoesters

Example R₉ D-2

D-3

D-4

D-5

D-6

D-7

D-8

D-9

D-10

D-11

D-12

D-13

D-14

D-15

D-16

D-17

D-18

D-19

D-20

D-21

D-22

D-23

D-24

D-25

D-26

D-27

D-28

D-29

D-30

D-31

D-32

D-33

D-34

D-35

D-36

D-37

D-38*

D-39

D-40

D-41

D-42

D-43

D-44

D-45

D-46

D-47

D-48

D-49

D-50

D-51

D-52**

[0595] The compounds from Table E above are named:

[0596] D-2: 5-Hydroxy-6-methyl-3-oxo-5-(2-thiazol-2-yl-ethyl)-heptanoicacid methyl ester;

[0597] D-3: 5-Hydroxy-6-methyl-3-oxo-5-(2-thiazol-4-yl-ethyl)-heptanoicacid methyl ester;

[0598] D-4: 5-Hydroxy-6-methyl-3-oxo-5-(2-thiazol-5-yl-ethyl)-heptanoicacid methyl ester;

[0599] D-5:5-Hydroxy-6-methyl-5-[2-(5-methyl-thiazol-2-yl)-ethyl]-3-oxo-heptanoicacid methyl ester;

[0600] D-6:5-Hydroxy-6-methyl-5-[2-(4-methyl-thiazol-2-yl)-ethyl]-3-oxo-heptanoicacid methyl ester;

[0601] D-7:5-Hydroxy-6-methyl-5-[2-(2-methyl-thiazol-4-yl)-ethyl]-3-oxo-heptanoicacid methyl ester;

[0602] D-8:5-Hydroxy-6-methyl-5-[2-(5-methyl-thiazol-4-yl)-ethyl]-3-oxo-heptanoicacid methyl ester;

[0603] D-9:5-Hydroxy-5-[2-(2-isopropyl-thiazol-4-yl)-ethyl]-6-methyl-3-oxo-heptanoicacid methyl ester;

[0604] D-10:5-Hydroxy-5-[2-(4-isopropyl-thiazol-5-yl)-ethyl]-6-methyl-3-oxo-heptanoicacid methyl ester;

[0605] D-11:5-Hydroxy-5-[2-(5-isopropyl-thiazol-4-yl)-ethyl]-6-methyl-3-oxo-heptanoicacid methyl ester;

[0606] D-12:5-Hydroxy-5-[2-(4-isopropyl-thiazol-2-yl)-ethyl]-6-methyl-3-oxo-heptanoicacid methyl ester;

[0607] D-13:5-[2-(2-Acetylamino-thiazol-4-yl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoicacid methyl ester;

[0608] D-14: 5-Hydroxy-6-methyl-3-oxo-5-(2-pyridin-2-yl-ethyl)-heptanoicacid methyl ester;

[0609] D-15: 5-Hydroxy-6-methyl-3-oxo-5-(2-pyridin-4-yl-ethyl)-heptanoicacid methyl ester;

[0610] D-16: 5-Hydroxy-6-methyl-3-oxo-5-(2-pyridin-3-yl-ethyl)-heptanoicacid methyl ester;

[0611] D-17: 5-(2-Furan-2-yl-ethyl)-5-hydroxy-6-methyl-3-oxo-heptanoicacid methyl ester;

[0612] D-18: 5-(2-Furan-3-yl-ethyl)-5-hydroxy-6-methyl-3-oxo-heptanoicacid methyl ester;

[0613] D-19:5-Hydroxy-6-methyl-3-oxo-5-[2-(tetrahydro-furan-2-yl)-ethyl]-heptanoicacid methyl ester;

[0614] D-20:5-Hydroxy-6-methyl-3-oxo-5-(2-thiophen-3-yl-ethyl)-heptanoic acid methylester;

[0615] D-21:5-Hydroxy-6-methyl-3′-oxo-5-(2-thiophen-2-yl-ethyl)-heptanoic acidmethyl ester;

[0616] D-22:5-{2-[2-(tert-Butyl-dimethyl-silanyloxymethyl)-thiophen-3-yl]-ethyl}-5-hydroxy-6-methyl-3-oxo-heptanoicacid methyl ester;

[0617] D-23:5-{2-[5-(tert-Butyl-dimethyl-silanyloxymethyl)-thiophen-3-yl]-ethyl}-5-hydroxy-6-methyl-3-oxo-heptanoicacid methyl ester;

[0618] D-24:5-{2-[5-(tert-Butyl-dimethyl-silanyloxymethyl)-thiophen-2-yl]-ethyl}-5-hydroxy-6-methyl-3-oxo-heptanoicacid methyl ester;

[0619] D-25:5-Hydroxy-5-[2-(5-hydroxymethyl-thiophen-3-yl)-ethyl]-6-methyl-3-oxo-heptanoicacid methyl ester;

[0620] D-26:5-Hydroxy-5-[2-(5-hydroxymethyl-thiophen-2-yl)-ethyl]-6-methyl-3-oxo-heptanoicacid methyl ester;

[0621] D-27:5-Hydroxy-5-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-methyl-3-oxo-heptanoicacid methyl ester;

[0622] D-28:5-[2-(3-Fluoro-2-methyl-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoicacid methyl ester;

[0623] D-29:5-[2-(2-Fluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoic acidmethyl ester;

[0624] D-30:5-[2-(4-Fluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoic acidmethyl ester;

[0625] D-31:5-Hydroxy-6-methyl-3-oxo-5-[2-(1-trityl-1H-pyrazol-3-yl)-ethyl]-heptanoicacid methyl ester;

[0626] D-32:5-Hydroxy-6-methyl-3-oxo-5-[2-(1H-pyrrol-3-yl)-ethyl]-heptanoic acidmethyl ester;

[0627] D-33:5-Hydroxy-5-[2-(1H-imidazol-4-yl)-ethyl]-6-methyl-3-oxo-heptanoic acidmethyl ester;

[0628] D-34:5-Hydroxy-6-methyl-3-oxo-5-(2-pyrimidin-5-yl-ethyl)-heptanoic acidmethyl ester;

[0629] D-35:5-[2-(2-Amino-pyrimidin-5-yl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoicacid methyl ester;

[0630] D-36:5-[2-(4-Cyano-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoic acidmethyl ester;

[0631] D-37:5-{2-[2-(tert-Butyl-dimethyl-silanyloxymethyl)-phenyl]-ethyl}-5-hydroxy-6-methyl-3-oxo-heptanoicacid methyl ester;

[0632] D-38:5-Hydroxy-5-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-methyl-3′-oxo-heptanoicacid methyl ester;

[0633] D-39:5-Hydroxy-5-[2-(1H-indol-5-yl)-ethyl]-6-methyl-3-oxo-heptanoic acidmethyl ester;

[0634] D-40:5-Hydroxy-6-methyl-3-oxo-5-{2-[2-(2.2.2-trifluoro-acetylamino)-thiazol-4-yl]-ethyl}-heptanoicacid methyl ester;

[0635] D-41:5-Hydroxy-6-methyl-5-[2-(4-methyl-thiophen-3-yl)-ethyl]-3-oxo-heptanoicacid methyl ester;

[0636] D-42:5-Hydroxy-6-methyl-5-[2-(3-methyl-thiophen-2-yl)-ethyl]-3-oxo-heptanoicacid methyl ester;

[0637] D-43:5-{2-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-thiophen-2-yl]-ethyl}-5-hydroxy-6-methyl-3-oxo-heptanoicacid methyl ester;

[0638] D-44:5-Hydroxy-5-[2-(3-hydroxymethyl-thiophen-2-yl)-ethyl]-6-methyl-3-oxo-heptanoicacid methyl ester;

[0639] D-45:5-[2-(2,6-Difluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3′-oxo-heptanoicacid methyl ester;

[0640] D-46:5-[2-(3,5-Difluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoicacid methyl ester;

[0641] D-47:5-[2-(2,4-Difluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoicacid methyl ester;

[0642] D-48:5-[2-(3,4,5-Trifluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoicacid methyl ester;

[0643] D-49:5-[2-(5-Fluoro-2-methyl-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoicacid methyl ester;

[0644] D-50:5-[2-(2-Ethyl-5-Fluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoicacid methyl ester;

[0645] D-51:5-{2-[2-(tert-Butyl-dimethyl-silanyloxymethyl)-4-fluoro-phenyl]-ethyl}-5-hydroxy-6-methyl-3-oxo-heptanoicacid methyl ester; and

[0646] D-52:5-Hydroxy-5-[2-(4-fluoro-2-hydroxymethyl-phenyl)-ethyl]-6-methyl-3-oxo-heptanoicacid methyl ester.

[0647] General Method 8. Preparation of the Intermediate4-Hydroxy-5,6-dihydro-pyran-2-ones

[0648] The aldol intermediate was dissolved in THF (1 volume) andtreated with 9 to 10 volumes of NaOH (0.1N-1.0N). The reaction wasstirred from 1 hour to 24 hours at room temperature. The base solutionwas extracted with Et₂O and then cooled to 0° C. The mixture wasacidified to pH 4 to 5 using HCl (0.1N to 6N) or acetic acid. Onoccasion, the product could be isolated by filtration. Alternatively theacidified extracts were extracted with EtOAc. The organic extracts werecombined, dried (MgSO₄) and concentrated. Purification was accomplishedby trituration from Et₂O or flash chromatography.

EXAMPLE E-1

[0649]4-Hydroxy-6-isopropyl-6-[2-(4-methyl-thiazol-5-yl)-ethyl]-5,6-dihydro-pyran-2-one

[0650] The title compound was prepared as described in General Method 8using the crude aldol product isolated in Example D-1, 20 mL of f THF,and 200 mL of 1.0N NaOH. The reaction mixture was stirred at roomtemperature for 2 hours, then poured over ice and acidified to pH 5.1.The solution was extracted with EtOAc, dried (MgSO₄), and concentrated.Purification by silica gel chromatography, eluting with 5:95MeOH:CH₂Cl₂, gave the title compound.

[0651]¹H NMR (DMSO-d₆): δ 0.87-0.90 (m, 6H), 1.82-1.96 (m, 2H),2.07-2.18 (m, 1H), 2.25 (s, 3H), 2.31 (d of ABX q, 1H), 2.60 (d of ABXq, 1H), 2.74-2.81 (m, 2H), 4.96 (s, 1H), 8.78 (s, 1H), 11.39 (s, 1H).

[0652] The following dihydropyrones were prepared from the correspondingaldol products from Examples D-1 to D-51. The 4-hydroxy-dihydropyronesexist in different forms depending upon the solvent. TABLE F

Preparation of Racemic 4-Hydroxy-Dihydropyrones

General Analytical Data Example Aryl R₁₀ Method (¹H NMR or MS) E-2

i-Propyl Gen. Method 8 MS (APCI): 268 (M + H) E-3

i-Propyl Gen. Method 8 MS (APCI): 268 (M + H) E-4

i-Propyl Gen. Method 8 MS (APCI): 268 (M + H) E-5

i-Propyl Gen. Method 8 MS (APCI): 282 (M + H) E-6

i-Propyl Gen. Method 8 MS (APCI): 282 (M + H) E-7

i-Propyl Gen. Method 8 MS (APCI): 282 (M + H) E-8

i-Propyl Gen. Method 8 MS (APCI): 282 (M + H) E-9

i-Propyl Gen. Method 8 MS (APCI): 310 (M + H) E-10

i-Propyl Gen. Method 8 MS (APCI): 310 (M + H) E-11

i-Propyl Gen. Method 8 MS (APCI): 310 (M + H) E-12

i-Propyl Gen. Method 8 MS (APCI): 310 (M + H) E-13

i-Propyl Gen. Method 8 MS (APCI): 325 (M + H) E-14

i-Propyl Gen. Method 8 MS (APCI): 262 (M + H) E-15

i-Propyl Gen. Method 8 (CDCl₃): δ 1.05(d, 6H), 1.7-1.9(m, 1H),2.0-2.2(m, 2H), 2.6-2.9(ABq, 2H), 2.7-2.8(m, 2H), 3.42(s, 2H), 7.05(d,2H), 8.5(d, 2H). E-16

i-Propyl Gen. Method 8 (CDCl₃): δ 1.00(d, 6H), 1.7-1.9(m, 1H),1.95-2.2(m, 2H), 2.6-2.8(ABq, 2H), 2.6-2.8(m, 2H), 3.40(s, 2H),7.15-7.25(m, 1H), 7.4-7.5(m, 1H), 8.4-8.5(s.m, 2H). E-17

i-Propyl Gen. Method 8 (CDCl₃): δ 1.1(dd, 6H), 1.7-1.9(m, 1H),2.0-2.2(m, 2H), 2.6-2.8(ABq, 2H), 2.7-2.9(m, 2H), 3.40(s, 2H), 6.0(m,1H), 6.30(m, 1H), 7.3(m, 1H). E-18

i-Propyl Gen. Method 8 (CDCl₃): δ 1.1(dd, 6H), 1.7-1.9(m, 1H),1.95-2.2(m, 2H), 2.5-2.7(m, 2H), 2.6-2.8(ABq, 2H), 3.40(s, 2H), 6.25(s,1H), 7.1(m, 1H), 7.18(m, 1H). E-19

i-Propyl Gen. Method 8 (CDCl₃): δ 0.8-2.2 (m, 15H), 2.65 (AB q, 2H),3.40(ABq, 2H), 3.60-3.90(m, 3H). E-20

i-Propyl Gen. Method 8 Mp 140-142.5° C. E-21

i-Propyl Gen. Method 8 (CDCl₃): δ 1.05 (d, 6H), 1.8-2.0(m, 1H),2.0-2.2(m, 2H), 2.6-2.8(ABq, 2H), 2.9-3.1(m, 2H), 3.40(s, 2H), 6.8(m,1H), 6.9(m, 1H), 7.15(m, 1H). E-22

i-Propyl Gen. Method 7 then Gen. Method 8 (CDCl₃): δ 1.1(d, 6H),1.8-2.0(m, 1H), 2.0-2.2(m, 2H), 2.6-2.8(ABq, 2H), 2.8-3.0(m, 2H),3.40(s, 2H), 4.75(s, 2H), 6.65(d, 1H), 6.8(d, 1H). E-23

i-Propyl Gen. Method 7 then Gen. Method 8 (CDCl₃): δ 1.0(dd, 6H),1.7-1.9(m, 2H), 2.0-2.2(m, 2H), 2.6-2.8(m, Abq, 4H), 3.40(s, 2H), 4.8(d,2H), 6.8(s, 1H), 6.9(s, 1H). E-24

i-Propyl Gen. Method 7 then Gen. Method 8 MS (APCI): 295 (M −H) E-25

i-Propyl Gen. Method 8 (DMSO-d₆): δ 0.90 (d, 3H), 0.92(d, 3H),1.73-1.90(m, 2H), 2.10-2.19(m, 4H), 2.28(d of ABX q, 1H), 2.58-2.65(m,3H), 4.97(s, 1H), 6.92-6.98(m, 2H), 7.08-7.15(m, 1H), 11.39(bs, 1H).E-26

i-Propyl Gen. Method 8 (DMSO-d₆): δ 0.89 (d, 3H), 0.91(d, 3H),1.81-1.95(m, 2H), 2.08-2.17(m, 1H), 2.28(d of ABX q, 1H), 2.58-2.64(m,3H), 4.96(s, 1H), 7.07-7.14(m, 2H), 7.19-7.28(m, 2H), 11.37(bs, 1H).E-27

i-Propyl Gen. Method 8 (DMSO-d₆): δ 0.88 (d, 3H), 0.90(d, 3H),1.82-1.91(m, 2H), 2.05-2.14(m, 1H), 2.32(d of ABXq, 1H), 2.54-2.62(m,3H), 4.96(s, 1H), 7.04-7.11(m, 2H), 7.18-7.22(m, 2H), 11.35(bs, 1H).E-28

i-Propyl Gen. Method 8 MS (APCI): 250 (M) E-29

i-Propyl Gen. Method 8 MS (APCI): 250(M + H) E-30

i-Propyl Gen. Method 8 MS (APCI): 493(M + H) E-31

i-Propyl Gen. Method 8 MS (APCI): 263(M + H) E-32

i-Propyl Gen. Method 8 MS (APCI): 278(M + H) E-33

i-Propyl Gen. Method 8 MS (APCI): 286(M + H) E-34

i-Propyl Gen. Method 8 MS (APCI): 290 (M) E-35

i-Propyl 08/883,743 E-36

Cyclopentyl E-37

Cyclohexyl E-38

i-Propyl E-39

Cyclopentyl E-40

Cyclohexyl E-41

i-Propyl E-42

Cyclopentyl From 08/883,743 E-43

Cyclohexyl From 08/883,743 E-44

i-Propyl From 08/883,743 E-45

Cyclopentyl From 08/883,743 E-46

Cyclohexyl From 08/883,743 E-47

i-Propyl Gen. Method 8 MS (APCI): 300(M + H) E-48

i-Propyl Gen. Method 8 MS (APCI): 379(M + H) E-49

i-Propyl Gen. Method 8 MS (APCI): 281(M + H) E-50

i-Propyl Gen. Method 8 MS (APCI): 281(M + H) E-51

i-Propyl Gen. Method 8 (CDCl₃): δ 1.02-1.06 (dd, 6H), 1.80-2.00(m, 1H),2.05-2.25(m, 2H), 2.61-2.79(ABq, 2H), 2.85-3.05(m, 2H), 3.34-3.52(AB q,2H), 4.60(d, 2H), 6.97(d, 1H), 7.10(d, 1H). E-52

i-Propyl Gen. Method 8 (CDCl₃) δ 0.88(d, 3H), 0.91(d, 3H), 1.74-1.94(m,2H), 2.10-2.19(m, 1H), 2.28(d of ABXq, 1 H), 2.58-2.65(m, 3 H), 4.97(s,1H), 6.92-6.98(m, 2H), 7.08-7.15(m, 1H), 11.39(bs, 1H) E-53

i-Propyl Gen. Method 8 (CDCl₃) δ 0.88(d, 3 H), 0.91(d, 3H), 1.87-1.93(m,2H), 2.04-2.13(m, 1H), 2.33(d of ABXq, 1 H), 2.60-2.69(m, 3 H), 4.96(s,1H), 7.00-7.04(m, 3H), 11.35(bs, 1H) E-54

i-Propyl Gen. Method 8 (DMSO) δ 0.89(d, 3 H), 0.91(d, 3H), 1.77-1.94(m,2H), 2.07-2.16(m, 1H), 2.29(d of ABXq, 1H), 2.57-2.63(m, 3H), 4.95(s,1H), 6.95-7.01(m, 1H), 7.11-7.19(m, 1H), 7.27-7.35(m, 1H), 11.36(bs, 1H)E-55

i-Propyl Gen. Method 8 (CDCl₃) δ 0.87(d, 3H), 0.89(d, 3H), 1.86-1.92(m,2H), 2.01-2.15(m, 1H), 2.34(d of ABXq, 1H), 2.53-2.61(m, 3H), 4.94(s,1H), 7.15-7.24(m, 2H), 11.36(bs, 1H). E-56

i-Propyl Gen. Method 8 (DMSO) δ 0.89 (d, 3 H), 0.91(d, 3H), 1.77-1.85(m,2H), 2.08-2.16(m+s, 4H), 2.29(d of ABXq, 1 H), 2.53-2.64(m, 3 H),4.96(s, 1H), 6.84-6.96(m, 2H), 7.10-7.15(m, 1H), 11.36(bs, 1H) E-57

i-Propyl Gen. Method 8 (DMSO) δ 0.89(d, 3 H), 0.91(d, 3H), 1.09 (t, 3H),1.80-1.87(m, 2H), 2.08-2.17(m, 1 H), 2.28(d of ABXq, 1H), 2.47-2.51(m,partially obscured by DMSO, 2H), 2.54-2.64(m, 3H), 4.96(s, 1H),6.88-6.95(m, 2 H), 7.15-7.18(m, 1 H), 11.38(bs, 1H). E-58

i-Propyl Gen. Method 8 E-59

i-Propyl Gen. Method 7 (from E-58) (DMSO) δ 0.95(d, 3 H), 0.93(d, 3H),1.84-1.94(m, 2H), 2.14-2.26(m, 1H), 2.35(d of ABXq, 1H), 2.53-2.62(m,partially obscured by DMSO, 2H), 2.66(d of ABXq, 1H), 4.52 (s, 2H),5.03(s, 1H), # 5.32(bs, 1H), 6.99-7.05(m, 1H), 7.15-7.22(m, 2H), 11.42(bs, 1H)

[0653] The compounds from Table F above are named:

[0654] E-2:4-Hydroxy-6-isopropyl-6-(2-thiazol-2-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0655] E-3:4-Hydroxy-6-isopropyl-6-(2-thiazol-4-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0656] E-4:4-Hydroxy-6-isopropyl-6-(2-thiazol-5-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0657] E-5:4-Hydroxy-6-isopropyl-6-[2-(5-methyl-thiazol-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0658] E-6:4-Hydroxy-6-isopropyl-6-[2-(4-methyl-thiazol-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0659] E-7:4-Hydroxy-6-isopropyl-6-[2-(2-methyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0660] E-8:4-Hydroxy-6-isopropyl-6-[2-(5-methyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0661] E-9:4-Hydroxy-6-isopropyl-6-[2-(2-isopropyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0662] E-10:4-Hydroxy-6-isopropyl-6-[2-(4-isopropyl-thiazol-5-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0663] E-11:4-Hydroxy-6-isopropyl-6-[2-(5-isopropyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0664] E-12:4-Hydroxy-6-isopropyl-6-[2-(4-isopropyl-thiazol-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0665] E-13:N-{4-[2-(4-Hydroxy-2-isopropyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-ethyl]-thiazol-2-yl}-acetamide;

[0666] E-14:4-Hydroxy-6-isopropyl-6-(2-pyridin-2-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0667] E-15:4-Hydroxy-6-isopropyl-6-(2-pyridin-4-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0668] E-16:4-Hydroxy-6-isopropyl-6-(2-pyridin-3-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0669] E-17:6-(2-Furan-2-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0670] E-18:6-(2-Furan-3-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0671] E-19:4-Hydroxy-6-isopropyl-6-[2-(tetrahydro-furan-2-yl)-5,6-dihydro-pyran-2-one;

[0672] E-20:4-Hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0673] E-21:4-Hydroxy-6-isopropyl-6-(2-thiophen-2-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0674] E-22:4-Hydroxy-6-[2-(5-hydroxymethyl-thiophen-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0675] E-23:4-Hydroxy-6-[2-(5-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0676] E-24:4-Hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0677] E-25:6-[2-(3-Fluoro-2-methyl-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0678] E-26:6-[2-(2-Fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0679] E-27:6-[2-(4-Fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0680] E-28:4-Hydroxy-6-isopropyl-6-[2-(1H-pyrazol-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0681] E-29:4-Hydroxy-6-isopropyl-6-[2-(1H-pyrrol-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0682] E-30:4-Hydroxy-6-isopropyl-6-[2-(1-trityl-1H-imidazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0683] E-31:4-Hydroxy-6-isopropyl-6-(2-pyrimidin-5-yl-ethyl)-5,6-dihydro-pyran-2-one;

[0684] E-32:6-[2-(2-Amino-pyrimidin-5-yl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0685] E-33:4-[2-(4-Hydroxy-2-isopropyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-ethyl]-benzonitrile;

[0686] E-34:4-Hydroxy-6-isopropyl-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-5,6-dihydro-pyran-2-one;

[0687] E-47:4-Hydroxy-6-[2-(1H-indol-5-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0688] E-48:2,2,2-Trifluoro-N-{4-[2-(4-hydroxy-2-isopropyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-ethyl]-thiazol-2-yl}-acetamide;

[0689] E-49:4-Hydroxy-6-isopropyl-6-[2-(4-methyl-thiophen-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0690] E-50:4-Hydroxy-6-isopropyl-6-[2-(3-methyl-thiophen-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0691] E-51:4-Hydroxy-6-[2-(3-hydroxymethyl-thiophen-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0692] E-52:6-[2-(2,6-Difluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0693] E-53:6-[2-(3,5-Difluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0694] E-54:6-[2-(2,4-Difluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0695] E-55:6-[2-(3,4,5-Trifluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0696] E-56:6-[2-(5-Fluoro-2-methyl-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0697] E-57:6-[2-(2-Ethyl-5-Fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0698] E-58:6-{2-[2-(tert-Butyl-dimethyl-silanyloxymethyl)-4-fluoro-phenyl]-ethyl}-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;and

[0699] E-59:6-[2-(4-Fluoro-2-hydroxymethyl-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one.

[0700] Alternate Synthesis of 4-Hydroxy-5,6-dihydro-pyran-2-ones viaβ-Hydroxyesters. General

[0701] Method 9. Preparation of β-Hydroxyesters from Ketones (Table D)or Enones (Table B)

[0702] Diisopropylamine (1.25-1.4 equiv.) was cooled to −10° C. andtreated with nBuLi (1.25 equiv.) over 10 to 20 minutes. The solution wasstirred for 15 to 45 minutes at −10° C. and then cooled to −60° C. to−78° C. The desired acetate (1.25 equiv.) was dissolved in THF and addeddropwise to the LDA solution over 30 to 90 minutes. When addition wascomplete, the reaction mixture was stirred at −78° C. to −40° C. foranother 30 to 90 minutes. The appropriate ketone (from Examples C-1 toC-39) or enone (from Examples B-1 to B-30) was dissolved in THF andadded over 15 to 30 minutes. The reaction mixture was warmed to roomtemperature and stirred for 3 to 18 hours. The solution was poured into1N HCl:ice; the product was extracted into EtOAc, dried (MgSO₄), andconcentrated. The product could be purified via chromatography orrecrystallization.

EXAMPLE F-1

[0703] 3-Hydroxy-4-methyl-3-(2-thiophen-3-yl-ethyl)-pentanoic AcidTert-Butyl Ester

[0704] The title compound was prepared as described in General Method 9using t-butyl acetate (42.6 mmol), diisopropyl amine (42.6 mmol), nBuLi(42.6 mmol), 4-methyl-1-thiophen-3-yl-pentan-3-one (Example C-5; 21.3mmol), and THF (100 mL). The title compound was purified by flashchromatography over silica gel eluting with hexane:EtOAc 97:3. ¹NMR(CDCl₃): δ 0.95 (dd, 6H), 1.47 (s, 9H), 1.7-2.0 (m, 3H), 2.36-2.54 (ABq, 2H), 2.6-2.8 (m, 2H), 6.93-6.95 (m, 2H), 7.23-7.25 (m, 1H).

[0705] The following hydroxyesters were prepared in similar fashion fromthe analogous ketones from Examples C-1 to C-57 or enones from ExamplesB-1 to B-36: TABLE G Preparation of Hydroxyesters

Analytical Data Example R₁₁ R₁₂ (¹H NMR or MS) F-2

CH₂Ph (CDCl₃): δ 0.94(d, 3H), 0.96(d, 3H), 1.79-1.88(m, 1H), 2.71(s,2H), 4.00(br s, 1H), 5.07(d, 1H), 5.14(d, 1H), 6.19(d, 1H), 6.58(d, 1H),6.90-6.70(m, 2H), 7.06-7.09(m, 1H), 7.24-7.29(m, 5H), 7.36-7.38(m, 1H).F-3

CH₂Ph F-4

CH₂Ph MS(APCI): 393(M+H) F-5

CH₂Ph MS(APCI): 393(M+H) F-6

CH₂Ph MS(APCI): 393(M+H) F-7

CH₂Ph MS(APCI): 411(M+H) F-8

CH₂Ph MS(APCI): 411(M+H) F-9

CMe₃ MS(APCI): 323(M+H) F-10

CMe₃ (CDCl₃): δ 0.95(d, 3H), 0.97(d, 3H), 1.48(s, 9H), 1.75-1.86(m, 2H),1.88-1.96(m, 1H), 2.40(d, 1H), 2.52(d, 1H), 2.63-2.73(m, 2H), 3.92(s,1H), 7.16-7.21(m, 3H), 7.26-7.31(m, 2H). F-11

CH₂Ph MS(APCI): 326(M+H) F-12

CH₂Ph (CDCl₃): δ 0.95(d, 3H), 0.96(d, 3H), 1.76-1.88(m, 1H), 2.71(s,2H), 3.98(bs, 1H), 5.05(d, 1H), 5.13(d, 1H), 6.10(d, 1H), 6.57(d, 1H),6.95-7.03(m, 2H), 7.23-7.31(m, 7H). F-13

Et (CDCl₃): δ 0.00(s, 9H), 0.83(s, 6H), 0.99(d, 6H), 1.3(t, 3H),1.7-2.0(m, 3H), 2.50(dd, 2H), 2.60(t, 2H), 3.71(s, 1H), 4.19(q, 2H),4.66(s, 2H), 6.91(d, 1H), 7.2(d, 1H). F-14

CMe₃ (CDCl₃): δ 0.93-0.97(t, 6H), 1.47(s, 9H), 1.6-1.80(m, 2H),1.91-1.95 (m, 1H), 2.37(s, 3H), 2.37-2.40(d, 1H), 2.48-2.51 (d, 1H),2.56-2.51(m, 2H), 3.92(s, 1H), 6.80(d, 1H), 6.99(d, 1H). F-15

CH₂Ph F-16

CH₂Ph (CDCl₃) δ 0.93(d, 3H), 0.95(d, 3H), 1.77-1.87(m, 1H), 2.70(s, 2H),4.00(s, 1H), 5.06(d, 1H), 5.15(d, 1H), 6.18(d, 1H), 6.52(d, 1H),6.64-6.71(m, 1H), 6.75-7.82(m, 2H), 7.24-7.38(m, 2H). F-17

CMe₃ (CDCl₃) δ 0.94(d, 3H), 0.96(d, 3H), 1.46(s, 9H), 1.60-1.75(m, 2H),1.89-1.97 *m, 1H), 2.309(s, 3H), 2.39 (d, 1H), 2.50(d, 1H), 2.56-2.67(m,2H), 3.97(s, 1H), 6.77-6.86(m, 2H), 7.04-7.08 (m, 1H).

[0706] The compounds of Table G above are named:

[0707] F-2: 5-(3-Fluoro-phenyl)-3-hydroxy-3-isopropyl-pent-4-enoic acidbenzyl ester;

[0708] F-3: 5-(3,4-Difluoro-phenyl)-3-hydroxy-3-isopropyl-pent-4-enoicacid benzyl ester;

[0709] F-4:3-Hydroxy-3-isopropyl-5-(2-trifluoromethyl-phenyl)-pent-4-enoic acidbenzyl ester;

[0710] F-5:3-Hydroxy-3-isopropyl-5-(3-trifluoromethyl-phenyl)-pent-4-enoic acidbenzyl ester;

[0711] F-6:3-Hydroxy-3-isopropyl-5-(4-trifluoromethyl-phenyl)-pent-4-enoic acidbenzyl ester;

[0712] F-7:5-(3-Fluoro-5-trifluoromethyl-phenyl)-3-hydroxy-3-isopropyl-pent-4-enoicacid benzyl ester;

[0713] F-8:5-(4-Fluoro-3-trifluoromethyl-phenyl)-3-hydroxy-3-isopropyl-pent-4-enoicacid benzyl ester;

[0714] F-9:3-Hydroxy-3-[2-(2-hydroxymethyl-phenyl)-ethyl]-4-methyl-pentanoic acidtert-butyl ester;

[0715] F-10: 3-Hydroxy-4-methyl-3-(2-phenyl-ethyl)-pentanoic acidtert-butyl ester;

[0716] F-11: 3-Hydroxy-3-isopropyl-5-phenyl-3-pent-4-enoic acid benzylester;

[0717] F-12: 5-(4-Fluoro-phenyl)-3-hydroxy-3-isopropyl-pent-4-enoic acidbenzyl ester;

[0718] F-13:3-{2-[4-(tert-Butyl-dimethyl-silanyloxymethyl)-thiophen-3-yl]-ethyl}-3-hydroxy-4-methyl-pentanoicacid ethyl ester;

[0719] F-14:3-Hydroxy-4-methyl-3-[2-(2-methyl-thiophen-3-yl)-ethyl]-pentanoic acidtert-butyl ester;

[0720] F-15:5-(3-Fluoro-2-methyl-phenyl)-3-hydroxy-3-isopropyl-pent-4-enoic acidbenzyl ester;

[0721] F-16: 5-(3,5-Difluoro-phenyl)-3-hydroxy-3-isopropyl-pent-4-enoicacid benzyl ester; and

[0722] F-17:5-(4-Fluoro-2-methyl-phenyl)-3-hydroxy-3-isopropyl-pent-4-enoic acidtert-butyl ester.

[0723] Separation of β-Hydroxy Ester Enantiomers via Chiral HPLC

EXAMPLE F-1 (S)

[0724] (S)-3-Hydroxy-4-methyl-3-(2-thiophen-3-yl-ethyl)-pentanoic AcidTert-Butyl Ester

[0725] The title compound was prepared by resolution on a Chiralpak ADcolumn eluting with 1:99 isopropanol:hexane to afford both enantiomersof 3-hydroxy-4-methyl-3-(2-thiophen-3-yl-ethyl)-pentanoic acidtert-butyl ester. The S enantiomer eluted first.

[0726]¹H NMR (CDCl₃): δ0.95 (dd 6H), 1.47 (s, 9H), 1.7-2.00 (m, 3H),2.36-2.54 (AB q, 2H), 2.6-2.8 (m, 2H), 6.93-6.95 (m, 2H), 7.23-7.25 (m,1H).

EXAMPLE F-1 (R)

[0727] (R)-3-Hydroxy-4-methyl-3-(2-thiophen-3-yl-ethyl)-pentanoic AcidTert-Butyl Ester

[0728] The title compound was prepared as described above via resolutionof Compound F-9 on a Chiralpak AD column eluting with 1:99isopropanol:hexane to afford both enantiomers of3-hydroxy-4-methyl-3-(2-thiophen-3-yl-ethyl)-pentanoic acid tert-butylester. The R enantiomer eluted second.

[0729]¹H NMR (CDCl₃): δ 0.95 (dd, 6H), 1.47 (s, 9H), 1.7-2.00 (m, 3H),2.36-2.54 (AB q, 2H), 2.6-2.8 (m, 2H), 6.93-6.95 (m, 2H), 7.23-7.25 (m,1H).

EXAMPLE F-9 (S)

[0730](S)-3-Hydroxy-4-methyl-3-[2-(2-hydroxymethyl-phenyl)-ethyl]-pentanoicAcid Tert-Butyl Ester

[0731] The title compound was prepared by resolution of Compound F-9 ona Chiralpak AD column eluting with isopropanol:hexane (1:99) to affordboth enantiomers of3-hydroxy-4-methyl-3-[2-(2-hydroxymethyl-phenyl)-ethyl)-pentanoic acidtert-butyl ester. MS (APCI): 323 (M+H).

EXAMPLE F-14 (S)

[0732](S)-3-Hydroxy-4-methyl-3-[2-(2-methyl-thiophen-3-yl)-ethyl]-pentanoicAcid Tert-Butyl Ester

[0733] The title compound was prepared by resolution on a Chiralpak ADcolumn eluting with 0.75:0.25:99 ethanol:isopropanol:hexane to affordboth enantiomers of3-hydroxy-4-methyl-3-[2-(2-methyl-thiophen-3-yl)-ethyl]-pentanoic acidtert-butyl ester. The S enantiomer eluted first.

[0734]¹H NMR (CDCl₃): δ 0.93-0.97 (t, 6H), 1.47 (s, 9H), 1.6-1.80 (m,2H), 1.91-1.95 (m, 1H), 2.37 (s, 3H), 2.37-2.40 (d, 1H), 2.48-2.51 (d,1H), 2.56-2.61 (m, 2H), 3.92 (s, 1H), 6.80 (d, 1H), 6.99 (d, 1H).

[0735] General Method 10. Preparation of β-Hydroxyacids

[0736] The appropriate β-hydroxyester (1 equiv.) was dissolved in EtOHand treated with 1.4 to 2.0 equivalents of an alkoxide (KOH or LiOH).The mixture was stirred at room temperature or heated to reflux for 4 to18 hours. The solution was concentrated to dryness, and the residue waspartitioned between H₂O and Et₂O. The aqueous layer was separated,acidified with 1N HCl, and extracted with Et₂O. The solution was dried(MgSO₄) and concentrated.

[0737] Alternatively, the benzyl esters (compounds F-2 through F-8 andcompounds F-11 and F-12) were hydrogenated as described in GeneralMethod 3 to give the corresponding acid.

EXAMPLE G-1 (S)

[0738] (S)-3-Hydroxy-4-methyl-3-(2-thiophen-3-yl-ethyl)-pentanoic Acid

[0739] The title compound was prepared as described in General Method 10using (S)-3-hydroxy-4-methyl-3-(2-thiophen-3-yl-ethyl)-pentanoic acidtert-butyl ester (Example F-1 (S); 8 mmol), LiOH (16 mmol), H₂O (5 mL),and MeOH (15 mL).

[0740]¹NMR (CDCl₃): δ 0.98 (t, 6H), 1.8-2.0 (m, 3H), 2.50-2.70 (Ab q,2H), 2.6-2.8 (m, 2H), 6.93-6.95 (m, 2H), 7.23-7.25 (m, 1H).

[0741] The following β-hydroxyacids were prepared from the correspondingesters, either by hydrolysis (General Method 10) or hydrogenolysis (asoutlined in General Method 3) as noted: TABLE H Synthesis ofβ-hydroxyacids

Analytical Data Example R₁₃ General Method Chirality (¹H NMR or MS) G-1(R)

Gen. Method 10 R (CDCl₃): δ 0.98(t, 6H), 1.80-2.0(m, 2H), 2.50-2.70(ABq, 2H), 2.6-2.8(m, 2H), 6.93-6.95(m, 2H), 7.23-7.25(m, 1H). G-1

Gen. Method 10 ± (CDCl₃): δ 0.92-0.95(m, 6H), 1.78-2.02(m, 3H),2.49-2.76(m, 4H), 6.91 (m, 2H), 7.22(m, 1H). G-2

Gen. Method 3 ± (CDCl₃): δ 0.95-1.00(m, 6H), 1.71-2.03(m, 3H),2.49-2.56(m, 1H), 2.62-2.73(m, 3H), 3.75-3.79(m, 1H), 6.84-6.91(m, 2H),6.96(d, 1H), 7.18-7.27(m, 1H). G-3

Gen. Method 3 ± (CDCl₃): δ 0.94-0.99(m, 6H), 1.78-1.89(m, 2H),1.92-2.01(m, 1H), 2.52(d, 1H), 2.61-2.70 (m, 3H), 3.75-3.79(m, 1H),6.85-6.91(m, 1H), 6.94-7.09(m, 2H). G-4

Gen. Method 3 ± MS(APCI): 303(M+H) G-5

Gen. Method 3 ± MS(APCI): 303(M+H) G-6

Gen. Method 3 ± MS(APCI): 607(M+H) G-7

Gen. Method 3 ± MS(APCI): 321(M+H) G-8

Gen. Method 3 ± MS(APCI): 321(M+H) G-9

Gen. Method 10 S MS(APCI): 266(M) Rotation: −3.8° (c = 2.0, EtOH) G-10

Gen. Method 10 (using F-10) or Gen. Method 3 (using F-11) ± (CDCl₃): δ0.97(d, 3H), 0.99(d, 3H), 1.80-1.93(m, 2H), 1.95-2.05(m, 2H), 2.56 (d,1H), 2.65-2.74(m, 3H), 7.17-7.21(m, 3H), 7.26-7.32(m, 2H). G-11

Gen. Method 3 ± (CDCl₃): δ 0.96(d, 3H), 0.99(d, 3H), 1.76-1.89(m, 2H),1.91-2.05(m, 1H), 2.55(d, 1H), 2.63-2.70 (m, 3H), 3.74-3.78(m, 1H),6.93-6.91(m, 2H), 7.11-7.16(m, 2H). G-12

Gen. Method 10 ± MS(APCI): 385(M+H) G-13

Gen. Method 10 S MS(APCI): 255 (M−H) G-14

Gen. Method 3 ± (CDCl₃) δ 0.97(d, 3H), 0.99(d, 3H), 1.66-1.86(m, 2H),1.96-2.05(m, 1H), 2.21(d, 3H), 2.59(d, 1H), 2.65-2.73(m, 3H),6.84-6.93(m, 2H), 7.03-6.10(m, 1H). G-15

Gen. Method 10 ± (CDCl₃) δ 0.96(d, 3H), 0.98(d, 3H), 1.81-1.86 (m, 2H),1.87-2.01(m, 1H), 2.53(d, 1H), 2.64-2.78(m, 3H), 3.74-3.78(m, 1H),6.59-6.67(m, 1H), 6.69-6.74(m, 2H). G-16

Gen. Method 10 ±

[0742] The compounds of Table H above are named:

[0743] G-2: 3-[2-(3-Fluoro-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoicacid;

[0744] G-3:3-[2-(3,4-Difluoro-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic acid;

[0745] G-4:3-Hydroxy-4-methyl-3-[2-(2-trifluoromethyl-phenyl)-ethyl]-pentanoicacid;

[0746] G-5:3-Hydroxy-4-methyl-3-[2-(3-trifluoromethyl-phenyl)-ethyl]-pentanoicacid;

[0747] G-6:3-Hydroxy-4-methyl-3-[2-(4-trifluoromethyl-phenyl)-ethyl]-pentanoicacid;

[0748] G-7:3-[2-(3-Fluoro-5-trifluoromethyl-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoicacid;

[0749] G-8:3-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoicacid;

[0750] G-9:(S)-3-Hydroxy-3-[2-(2-hydroxymethyl-phenyl)-ethyl]-4-methyl-pentanoicacid;

[0751] G-10: 3-Hydroxy-4-methyl-3-(2-phenyl-ethyl)-pentanoic acid;

[0752] G-11: 3-[2-(4-Fluoro-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoicacid;

[0753] G-12:3-{2-[4-(tert-Butyl-dimethyl-silanyloxy-methyl)-thiophen-3-yl]-ethyl}-3-hydroxy-4-methyl-pentanoicacid;

[0754] G-13:3-Hydroxy-4-methyl-3-[2-(2-methyl-thiophen-3-yl)-ethyl]-pentanoic acid;

[0755] G-14:3-[2-(3-Fluoro-2-methyl-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoicacid;

[0756] G-15:3-[2-(3,5-Difluoro-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic acid; and

[0757] G-16:3-[2-(4-Fluoro-2-methyl-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoicacid.

[0758] Resolution of Racemic β-hydroxyacids enantiomers

EXAMPLE G-2 (R)

[0759] (R)-3-[2-(3-Fluoro-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoicAcid

[0760] Racemic compound G-2 (42.0 g, 165 mmol) from Table H wasdissolved in 410 mL EtOAc and treated with (S)-α-methylbenzylamine(10.01 g, 82.58 mmol). The resulting slurry was placed on a steam bathand heated to reflux to dissolve the solids completely. The solution wasallowed to cool to room temperature slowly overnight. The flask was thencooled to 5° C., and the solids were filtered and washed with cold EtOAcand Et₂O. The product was recrystallized from hot EtOAc (110 mL) on asteam bath, and then cooled slowly to room temperature overnight. Theflask was then cooled (5° C.); the solids were filtered and washed withcold EtOAc followed by Et₂O to yield the desired compound. HPLC analysisof isolated solid (as the free acid): (AD chiralpak column, 1 mL/min.,97.5% Hexanes:2.5% IPA+0.1% TFA)

[0761] retention time:

[0762] 19.60 min. (95.3%)

[0763] 22.67 min. (4.7%)

EXAMPLE G-2 (S)

[0764] (S)-3-[2-(3-Fluoro-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoicAcid

[0765] A second solid was isolated from the mother liquor from ExampleG-2 (R) after the solution was allowed to stand for 48 hours. Themixture was cooled to 0° C. in ice bath for several hours. The solid wasfiltered off and washed with cold EtOAc followed by Et₂O. HPLC analysisof isolated solid (as the free acid): (AD chiralpak column, 1 mL/min.,97.5% Hexanes:2.5% IPA+0.1% TFA)

[0766] retention time:

[0767] 18.11 min. (11.76%)

[0768] 19.28 min. (88.24%).

[0769] The isolated solid was recrystallized from hot EtOAc (˜100 mL) ona steam bath and cooled slowly to room temperature overnight. Themixture then was cooled in an ice bath for 2 hours. The resulting solidswere filtered and washed with cold EtOAc followed by Et₂O to give thedesired enantiomer. The free acid was obtained by treating the salt with1N HCl followed by extraction with EtOAc. The organic phased was washedwith brine, dried (MgSO₄), filtered and concentrated to afford theresolved β-hydroxy acid. HPLC analysis of isolated solid (as the freeacid): (AD chiralpak column, 1 mL/min., 97.5% Hexanes:2.5% IPA+0.1% TFA)

[0770] retention time:

[0771] 18.20 min. (3.4%)

[0772] 19.42 min. (96.6%)

EXAMPLE G-3 (R)

[0773](R)-3-[2-(3,4-Difluoro-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic Acid

[0774] Compound G-3 (16.0 g, 58.8 mmol) from Table H was dissolved in150 mL EtOAc and treated with (S)-α-methylbenzylamine (3.77 g, 31.14mmol). The thick suspension that resulted was placed on a steam bath andheated to reflux. Additional EtOAc (240 mL) was added, followed by hotisopropanol (approximately 80 mL), until the solids dissolved. Thesolution was allowed to cool to room temperature slowly overnight. Themixture was then cooled to approximately 0° C. The resulting solids werefiltered and washed with cold EtOAc followed by Et₂O to yield thedesired enantiomer. HPLC analysis of isolated solid (as the free acid):(AD chiralpak column, 1 mL/min., 97.5% Hexanes:2.5% IPA+0.1% TFA)

[0775] retention time:

[0776] 23.80 min. (7.7%)

[0777] 25.10 min. (92.3%).

[0778] The isolated solid was dissolved in hot IPA (120 mL) and EtOAc(600 mL) on a steam bath and then cooled slowly to room temperatureovernight. The flask was cooled in an ice bath for several hours andthen filtered. The solids were washed with cold EtOAc followed by Et₂Oto yield the pure stereoisomer. The free acid was obtained by treatingthe salt with 1N HCl followed by extraction with EtOAc. The organicphased was washed with brine, dried (MgSO₄), filtered and concentratedto afford the resolved P-hydroxy acid. HPLC analysis of isolated solid(as the free acid): (AD chiralpak column, 1 mL/min., 97.5% Hexanes:2.5%IPA+0.1% TFA) retention time: 25.90 min. (>99%).

EXAMPLE G-3 (S)

[0779](S)-3-[2-(3,4-Difluoro-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic Acid

[0780] The mother liquor from the isolation of diastereomaric salt G-3(R) was treated with 1N HCl and extracted with EtOAc. The organic phasedwas washed with brine, dried (MgSO₄), filtered and concentrated toliberate compound G-3. HPLC analysis indicated the isolated material was78% (S):22% (R) based on comparison with previously isolated solid(diastereomaric salt G-3 (R)). β-Hydroxy acid G-3 (9.75 g, 35.8 mmol)was dissolved in 100 mL EtOAc and treated with (R)-α-methylbenzylamine(3.25 g, 26.86 mmol). The resulting thick suspension was placed on asteam bath and heated to reflux. Additional EtOAc (50 mL) was added,followed by hot IPA (100 mL), a little at a time until the solidsdissolved. The solution was allowed to cool to room temperatureovernight. The mixture was then cooled to 0° C. in an ice bath. Theresulting solids were filtered and washed with cold EtOAc followed byEt₂O. The free acid was obtained by treating the salt with 1N HClfollowed by extraction with EtOAc. The organic phased was washed withbrine, dried (MgSO₄), filtered and concentrated to afford the resolvedβ-hydroxy acid. HPLC analysis of isolated material (as the free acid):(AD chiralpak column, 1 mL/min., 97.5% Hexanes:2.5% IPA+0.1% TFA)

[0781] retention time:

[0782] 22.06 min. (96.9%)

[0783] 24.34 min. (3.1%).

Example G-10 (S)

[0784] (S)-3-Hydroxy-4-methyl-3-(2-phenyl-ethyl)-pentanoic Acid

[0785] Compound G-10 (15.0 g, 63.48 mmol) was dissolved in 155 mL EtOAcand treated with (S)-a-methylbenzylamine (4.23 g, 34.91 mmol). Theresulting slurry was placed on a steam bath and heated to reflux atwhich all solids dissolved. The solution allowed to cool to roomtemperature slowly overnight, then cooled to −20° C. Cold EtOAc wasadded, and the solids were filtered and washed with cold EtOAc and Et₂Oto yield the title compound. The free acid was obtained by treating thesalt with 1N HCl followed by extraction with EtOAc. The organic phasedwas washed with brine, dried (MgSO₄), filtered and concentrated toafford the resolved β-hydroxy acid. HPLC analysis of isolated solid (asthe free acid): (OD chiralpak column, 1 mL/min., 97.5% Hexanes:2.5%IPA:+0.1% Formic acid)

[0786] retention time:

[0787] 20.67 min. (4.4%)

[0788] 22.24 min. (95.6%).

EXAMPLE G-10 (R)

[0789] (R)-3-Hydroxy-4-methyl-3-(2-phenyl-ethyl)-pentanoic Acid

[0790] The mother liquor from the isolation of diastereomeric salt G-10(S) was treated with 1N HCl and extracted with EtOAc. The organic phasewas washed with brine, dried (MgSO₄), filtered and concentrated toliberate the free β-hydroxy acid. HPLC analysis indicated the isolatedmaterial was 73% (R):27% (S). β-Hydroxy acid G-10 (1 equiv.) wasdissolved in 600 mL EtOAc and treated with (R)-α-methylbenzylamine (0.74equiv.). The resulting suspension was placed on a steam bath and heatedto reflux. The solution was allowed to cool to room temperature slowlyand then cooled to 0° C. in an ice bath. The resulting solids werefiltered off and washed with cold EtOAc followed by Et₂O to yield thetitle compound. The free acid was obtained by treating the salt with 1NHCl followed by extraction with EtOAc. The organic phased was washedwith brine, dried (MgSO₄), filtered and concentrated to afford theresolved β-hydroxy acid. HPLC analysis of isolated solid (as the freeacid): (OD chiralpak column, 1 mL/min., 97.5% Hexanes:2.5% IPA:+0.1%Formic acid)

[0791] retention time:

[0792] 21.86 min. (95.6%)

[0793] 23.75 min. (4.4%).

EXAMPLE G-11 (R)

[0794] (R)-3-[2-(4-Fluoro-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoicAcid

[0795] Compound G-11 (37.1 g, 146 mmol) was dissolved in 375 mL EtOAcand treated with (S)-α-methylbenzylamine (4.23 g, 34.9 mmol). Theresulting slurry was heated to reflux, diluted with an additional 50 to100 mL EtOAc, and treated with hot isopropanol until the solids hadcompletely dissolved. The solution was allowed to cool to roomtemperature slowly and then cooled to 0° C. in an ice bath for ˜1 hour.Cold EtOAc was added; the solids were filtered off and washed with coldEtOAc and Et₂O to yield the title compound. HPLC analysis of isolatedsolid (as the free acid): (AS chiralpak column, 1 mL/min., 98%Hexanes:2% IPA:+0.1% Formic acid)

[0796] retention time:

[0797] 16.81 min. (7.52%)

[0798] 21.42 min. (92.48%).

[0799] The isolated solid and 450 mL EtOAc was heated to reflux andtreated with hot isopropanol until the solids dissolved. The solutionwas allowed to cool to room temperature slowly overnight. The flask wasthen cooled to −10 to −15° C. and treated with cold EtOAc. The solidswere filtered off and washed with cold EtOAc and Et₂O to yield the titlecompound. The free acid was obtained by treating the salt with 1N HClfollowed by extraction with EtOAc. The organic phased was washed withbrine, dried (MgSO4), filtered and concentrated to afford the resolvedβ-hydroxy acid. HPLC analysis of isolated solid (as the free acid): (ASchiralpak column, 1 mL/min., 98% Hexanes:2% IPA:+0.1% Formic acid)

[0800] retention time:

[0801] 16.74 min. (1.19%)

[0802] 20.95 min. (98.81%).

EXAMPLE G-11(S)

[0803] (S)-3-[2-(4-Fluoro-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoicAcid

[0804] The mother liquors from the isolation of the G-11 (R) enantiomerwere combined, treated with 1N HCl and extracted with EtOAc. The organicphase was washed with brine, dried (MgSO₄), filtered and concentrated toliberate the free β-hydroxy acid. HPLC analysis indicated the isolatedmaterial was 79% (S):21% (R). β-Hydroxy acid G-11 (22.6 g, 89.0 mmol)was dissolved in 250 mL EtOAc and treated with (R)-α-methylbenzylamine(9.17 g, 75.64 mmol). The resulting mixture was placed on a steam bath,heated to reflux, diluted with additional ˜100 mL EtOAc, and treatedwith hot isopropanol until solids completely dissolved. The solution wasallowed to cool to room temperature slowly overnight and then cooled to−10 to −15° C. Cold EtOAc was added; the solids were filtered off andwashed with cold EtOAc and Et₂O to yield the title compound. The freeacid was obtained by treating the salt with 1N HCl followed byextraction with EtOAc. The organic phased was washed with brine, dried(MgSO₄), filtered and concentrated to afford the resolved β-hydroxyacid. HPLC analysis of isolated solid (as the free acid): (AS chiralpakcolumn, 1 mL/min., 98% Hexanes:2% IPA:+0.1% Formic acid)

[0805] retention time:

[0806] 16.61 min. (96.17%)

[0807] 20.77 min. (3.83%).

EXAMPLE G-14 (S)

[0808](S)-3-[2-(3-Fluoro-2-methyl-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoicAcid

[0809] Compound G-14 (28.3 g, 105 mmol) was dissolved in 270 mL EtOAcand treated with (R)-α-methylbenzylamine (6.52 g, 53.8 mmol). Noprecipitate formed. After 2 hours the solvent was evaporated. To theresulting residue was added 200 mL hexanes, and the flask was refluxedon a steam bath until the solids dissolved. Et2O (20 mL) was added andthe solution allowed to cool to room temperature slowly overnight. Theresulting solids were filtered off and washed with cold hexanes/Et₂O.HPLC analysis of isolated solid (as the free acid): (AS chiralpakcolumn, 0.8 mL/min., 98% Hexanes/2% IPA/+0.1% Formic acid).

[0810] retention time:

[0811] 16.38 min. (80.76%)

[0812] 22.67 min. (19.24%)

[0813] The isolated solids, Et₂O (100 mL), and hexanes (200 mL) wereheated to reflux on a steam bath. EtOAc was added until all solidsdissolved (approximately 150 mL). An additional 200 mL of hexanes wereadded, and the mixture was brought back to reflux and then allowed tocool slowly to room temperature overnight. The flask was then cooled toapprox. 5° C. for 2 hours. The resulting solids were filtered and washedwith cold Et₂O to yield the title compound. HPLC analysis of isolatedsolid (as the free acid): (AS chiralpak column, 1 mL/min., 98%Hexanes/2% IPA/+0.1% Formic acid).

[0814] retention time:

[0815] 12.12 min. (94.8%)

[0816] 24.10 min. (5.2%)

EXAMPLE G-15 (S)

[0817](S)-3-[2-(3,5-Difluoro-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic Acid

[0818] Compound G-15 (24.6 g, 90.5 mmol) was dissolved in 235 mL EtOAcand treated with (R)-α-methylbenzylamine (6.03 g, 49.8 mmol). Theresulting slurry was placed on a steam bath and heated to reflux untilall solids dissolved. The solution was allowed to cool and hexanes wereadded (approximately 100 mL). The solution was returned to reflux, thesteam turned off, and the mixture allowed to cool to room temperatureovernight. The flask was then cooled to approx. 5° C. for 1 hour. Theresulting solids were filtered and washed with cold Et2O. HPLC analysisof isolated solid (as the free acid): (AS chiralpak column, 1.0 mL/min.,98% Hexanes/2% IPA/+0.1% Formic acid).

[0819] retention time:

[0820] 12.51 min. (92.3%)

[0821] 14.83 min. (7.7%)

[0822] The solids were suspended in EtOAc (approximately 300 mL) andheated to reflux on a steam bath. When the solids did not dissolve,isopropanol (approximately 20 mL) was added gradually until the materialcompletely dissolved. An additional 100 mL of EtOAc was added; themixture was brought back to reflux and then allowed to cool to roomtemperature overnight. The flask was then cooled to approx. 5° C. for 2hours. The resulting solids were filtered and washed with cold Et₂O toyield the title compound. HPLC analysis of isolated solid (as the freeacid): (AS chiralpak column, 1 mL/min., 98% Hexanes/2% IPA/+0.1% Formicacid).

[0823] retention time:

[0824] 12.65 min. (98.0%)

[0825] 15.10 min. (2.0%)

EXAMPLE G-16 (S)

[0826](S)-3-[2-(4-Fluoro-2-methyl-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoicAcid

[0827] Compound G-16 (enriched—62% (S)-enantiomer/38% (R) enantiomer)(11.1 g, 41.5 mmol) was dissolved in 120 mL EtOAc and treated with(S)-α-methylbenzylamine (6.52 g, 53.79 mmol). The resulting suspensionwas heated to reflux until all solids dissolved, at which time thesolution was allowed to cool to room temperature overnight. The reactionflask was cooled to 0° C. for 1 hour. The resulting solids were filteredoff and washed with cold Et₂O. HPLC analysis of isolated solid (as thefree acid): (AS chiralpak column, 0.8 mL/min., 98% Hexanes/2% IPA/+0.1%Formic acid).

[0828] retention time:

[0829] 15.86 min. (79.43%)

[0830] 19.34 min. (20.57%)

[0831] The isolated solids were suspended in EtOAc (150 mL) andisopropanol (10 mL) and heated to reflux on a steam bath until allsolids dissolved. The solution was allowed to cool to room temperatureovernight and then cooled to 0° C. for 1 hour. The resulting solids werefiltered off and washed with cold Et₂O to afford the title compound.HPLC analysis of isolated solid (as the free acid): (AS chiralpakcolumn, 0.8 mL/min., 98% Hexanes/2% IPA/+0.1% Formic acid).

[0832] retention time:

[0833] 15.83 min. (92.0%)

[0834] 19.34 min. (8.0%)

[0835] The isolated solids in EtOAc (130 mL) and isopropanol (6 mL) wereagain heated to reflux on a steam bath until the solids dissolved. Thesteam was shut off, and the solution was allowed to cool to roomtemperature overnight. The reaction flask was cooled to 0° C. for 1hour. The resulting solids were filtered off and washed with cold Et₂Oto afford the title compound. HPLC analysis of isolated solid (as thefree acid): (AS chiralpak column, 0.8 mL/min., 98% Hexanes/2% IPA/+0.1%Formic acid).

[0836] retention time:

[0837] 15.83 min. (96.7%)

[0838] 19.34 min. (3.3%)

EXAMPLE H

[0839] Bis [3-methoxy-3-oxopropanoato-(1-)—O,O']magnesate

[0840] Monomethyl malonate (2.39 g, 20 mmol) and magnesium ethoxide(1.16 g, 10 mmol) in THF (50 mL) were stirred for 3 hours at roomtemperature. The solution was concentrated under vacuum to give thetitle compound. The product was carried on crude to the next step.

[0841] General Method 11. Preparation of Chiral (or Racemic) β-Ketoesterfrom β-Hydroxy Acid for the Alternate Synthesis of intermediate4-Hydroxy-5,6-dihydro-pyran-ones

[0842] A solution of the chiral β-hydroxyacid as isolated above (or theracemic entity from Table H) (1.0 equiv.), THF (30 mL), andcarbonyldiimidazole (1.2-3 equiv.) was stirred for 3 to 18 hours at roomtemperature. Bis [3-methoxy-3-oxopropanoato (1-)—O,O′] magnesate fromExample H (1 to 2 equiv.) was added, and the reaction was stirred for 6to 72 hours at room temperature. The reaction was concentrated and theresidue partitioned between EtOAc and 1N HCl. The organic layer waswashed with aqueous NaHCO₃ and brine, dried (MgSO₄) and concentrated.Purification was accomplished by silica gel chromatography;alternatively, the material could be carried on crude.

EXAMPLE I-1 (S)

[0843] (S)-5-Hydroxy-6-methyl-3-oxo-5-(2-thiophen-3-yl-ethyl)-heptanoicAcid Ethyl Ester

[0844] The title compound was prepared as described in General Method 11using (S)-3-hydroxy-4-methyl-3-(2-thiophen-3-yl-ethyl)-pentanoic acid(from Example G-1 (S); 7.81 mmol), carbonyl diimidazole (8.59 mmol), bis[3-methoxy-3-oxopropanoato(1-)-O,O′]magnesate (15.62 mmol) and THF (85mL). Purification was accomplished using silica gel chromatography,eluting with 100% CH₂Cl₂.

[0845]¹H NMR (CDCl₃): δ 0.94 (dd, 6H), 1.27 (t, 3H), 1.75-190 (m, 2H),1.9-2.0 (m 1H), 2.65-2.75 (m, 3H), 2.80 (d, 1H), 3.48 (s, 2H), 4.15-4.25(m, 2H), 6.93 (m, 2H), 7.2-7.3 (m, 1H).

EXAMPLE I-2 (S)

[0846] 5-[2-(3-Fluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoicAcid Ethyl Ester, (S) Enantiomer

[0847] The title compound was prepared following General Method 11 fromcompound G-2 (S) (5.85 g, 23.00 mmol) and CDI (8.21 g, 50.61 mmol) in100 mL of THF. After 3.5 hours stirring under N₂ at room temperature,bis [3-methoxy-3-oxopropanoato(1-)-O,O′]magnesate (13.94 g, 48.31 mmol)was added, and the mixture was stirred at room temperature overnight.The product was purified via silica gel chromatography, eluting with 4:1hexanes:EtOAc to afford the title compound.

[0848]¹H NMR (CDCl₃): δ 0.93 (d, 3H), 0.95 (d, 3H), 1.27 (m, 3H),1.77-1.83 (m, 2H), 1.91-2.01 (m, 1H), 2.63-2.69 (m, 2H), 2.71 (d, 1H),2.83 (d, 1H), 3.48 (s, 2H), 3.61 (s, 1H), 4.19 (m, 2H), 6.84-6.90 (m,2H), 6.95 (d, 1H), 7.19-7.24 (m, 1H).

[0849] The following β-ketoesters were prepared in similar fashion fromthe appropriate chiral (or racemic—Examples G-1 to G-16) β-ketoacids:TABLE I Preparation of β-Ketoesters

Analytical Data Example R₁₄ Chirality (¹H NMR or MS) I-1 (R)

R (CDCl₃): δ 0.94(dd, 6H), 1.27(t, 3H), 1.75-1.90(m, 2H), 1.9-2.0(m,1H), 2.65-2.75(m, 3H), 2.80(d, 1H), 3.48(s, 2H), 4.15-4.25(m, 2H),6.93(m, 2H), 7.2-7.3(m, 1H). I-2 (R)

R I-3 (R)

R (CDCl₃): δ 0.93(d, 3H), 0.95(d, 3H), 1.27(m, 3H), 1.77(m, 2H),1.90-2.00(m, 1H), 2.62(m, 2H), 2.70(d, 1H), 2.83(d, 1H), 3.48(d, 2H),3.61(s, 1H), 4.19(m, 2H), 6.85-6.90(m, 1H), 6.94-7.09(m, 2H). I-3 (S)

S I-4

± MS(APCI): 373(M−H) I-5

± MS(APCI): 373(M−H) I-6

± MS(APCI): 373(M−H) I-7

± MS(APCI): 391(M−H) I-8

± MS(APCI): 391(M−H) I-9 (S)

S I-10 (S) Ph S (CDCl₃): δ 0.93(d, 3H), 0.96(d, 3H), 1.26(t, 3H),1.79-1.85(m, 2H), 1.93-2.02(m, 1H), 2.64-2.69(m, 2H), 2.72(d, 1H),2.83(d, 1H), 3.48(d, 2H), 4.18(q, 2H), 7.15-7.20(m, 3H), 7.26-7.31(m,2H). I-10 (R) Ph R (CDCl₃): δ 0.93(d, 3H), 0.96(d, 3H), 1.26(t, 3H),1.79-1.85(m, 2H), 1.93-2.02(m, 1H), 2.64-2.69(m, 2H), 2.72(d, 1H),2.83(d, 1H), 3.47(s, 2H), 4.19(q, 2H), 7.15-7.20(m, 3H), 7.25-7.31(m,2H). I-11 (R)

R (CDCl₃): δ 0.93(d, 3H), 0.95(d, 3H), 1.26(t, 3H), 1.75-1.81(m, 2H),1.91-2.01(m, 1H), 2.64-2.69(m, 2H), 2.71(d, 1H), 2.83(d, 1H), 3.48(s,2H), 4.18(q, 2H), 6.92-6.98(m, 2H), 7.10-7.15(m, 2H). I-11 (S)

S (CDCl₃): δ 0.93(d, 3H), 0.95(d, 3H), 1.26(t, 3H), 1.75-1.81(m, 2H),1.91-2.00(m, 1H), 2.60-2.68(m, 2H), 2.71(d, 1H), 2.83(d, 1H), 3.48(s,2H), 4.18(q, 2H), 6.92-6.98(m, 2H), 7.10-7.15(m, 2H). I-12

± I-13 (S)

S MS(APCI): 325(M−H) I-14 (S)

S (CDCl₃) δ 0.94(d, 3H), 0.96(d, 3H), 1.25(q, 3H), 1.69-1.76(m, 2H),1.95-2.04(m, 1H), 2.12(d, 3H), 2.64-2.70(m, 2H), 2.72(d, 1H), 3.48(s,2H), 3.61(s, 1H), 4.14-4.24(m, 2H), 6.82-6.92(m, 2H), 7.02-7.10(m, 1H).I-15 (S)

S I-16 (S)

S

[0850] The compounds of Table I above are named.

[0851] I-2:(R)-5-[2-(3-Fluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoicacid ethyl ester;

[0852] I-3:5-[2-(3,4-Difluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoicacid ethyl ester (R and S isomers);

[0853] I-4:5-Hydroxy-6-methyl-3-oxo-5-[2-(2-trifluoromethyl-phenyl)-ethyl]-heptanoicacid ethyl ester;

[0854] I-5:5-Hydroxy-6-methyl-3-oxo-5-[2-(3-trifluoromethyl-phenyl)-ethyl]-heptanoicacid ethyl ester;

[0855] I-6:5-Hydroxy-6-methyl-3-oxo-5-[2-(4-trifluoromethyl-phenyl)-ethyl]-heptanoicacid ethyl ester;

[0856] I-7:5-[2-(3-Fluoro-5-trifluoromethyl-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoicacid ethyl ester;

[0857] I-8:5-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoicacid ethyl ester;

[0858] I-9:(S)-5-Hydroxy-5-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-methyl-3-oxo-heptanoicacid ethyl ester;

[0859] I-10: 5-Hydroxy-6-methyl-3-oxo-5-(2-phenyl-ethyl)-heptanoic acidethyl ester (R and S isomers);

[0860] I-11:5-[2-(4-Fluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoic acidethyl ester (S and R isomers);

[0861] I-12:5-{2-[4-(tert-Butyl-dimethyl-silanyloxymethyl)-thiophen-3-yl]-ethyl}-5-hydroxy-6-methyl-3-oxo-heptanoicacid ethyl ester;

[0862] I-13:(S)-5-Hydroxy-6-methyl-5-[2-(2-methyl-thiophen-3-yl)-ethyl]-3-oxo-heptanoicacid ethyl ester;

[0863] I-14:(S)-5-[2-(3-Fluoro-2-methyl-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoicacid ethyl ester;

[0864] I-15:(S)-5-[2-(3,5-Difluoro-2-methyl-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoicacid ethyl ester; and

[0865] I-16:(S)-5-[2-(4-Fluoro-2-methyl-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoicacid ethyl ester.

[0866] Alternate Synthesis of the Intermediate4-Hydroxy-5,6-dihydro-pyran-2-ones (for both chiral and racemicintermediates)

EXAMPLE J-1 (S)

[0867](S)-4-Hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one

[0868] The title compound was prepared as described in General Method 8using (S)-hydroxy-6-methyl-3-oxo-5-(2-thiophen-3-yl-ethyl)-heptanoicacid ethyl ester (6.4 mmol), 0.1N NaOH (400 mL), and THF (40 mL). Theproduct was triturated from Et₂O, mp 117-123° C.

[0869] The following chiral dihydropyrones were prepared in a similarfashion: TABLE J Synthesis of Chiral Dihydropyrones (cont'd)

Analytical Data Example R₁₅ Chirality (¹H NMR or MS) J-1 (R)

R mp 117-123° C. J-2 (S)

S (DMSO-d₆): δ 0.88(d, 3H), 0.90(d, 3H), 1.89-1.93(m, 2H), 2.08-2.15(m,1H), 2.32(d, 1H), 2.56-2.62(m, 3H), 4.96(s, 1H), 6.95-7.04(m, 3H),7.27-7.33(m, 1H), 11.37(bs, 1H). J-2 (R)

R (DMSO-d₆): δ 0.88(d, 3H), 0.90(d, 3H), 1.88-1.93(m, 2H), 2.05-2.15(m,1H), 2.33(d, 1H), 2.56-2.62(m, 3H), 4.96(s, 1H), 6.96-7.04(m, 3H),7.26-7.33(m, 1H), 11.36(bs, 1H). J-3 (S)

S (DMSO-d₆): δ 0.87(d, 3H), 0.90(d, 3H), 1.86-1.91(m, 2H), 2.04-2.13(m,1H), 2.33(d, 1H), 2.55-2.61(m, 3H), 4.95(s, 1H), 6.99-7.03(m, 1H),7.24-7.34(m, 2H). J-3 (R)

R (DMSO-d₆): δ 0.87(d, 3H), 0.90 (d, 3H), 1.86-1.91(m, 2H), 2.04-2.13(m,1H), 2.33(d, 1H), 2.55-2.61(m, 3H), 4.95(s, 1H), 6.99-7.03(m, 1H),7.24-7.34(m, 2H). J-4

± MS(APCI): 329(M+H) J-5

± MS(APCI): 329(M+H) J-6

± MS(APCI): 329(M+H) J-7

± MS(APCI): 347(M+H) J-8

± MS(APCI): 347(M+H) J-9

S (CDCl₃): δ 1.05(d, 3H), 1.06(d, 3H), 1.8(br.s, 1H), 1.9(m, 1H),2.03(m, 1H), 2.23(m, 1H), 2.66(d, 1H), 2.78(d, 1H), 2.81(m, 2H), 3.4(d,1H), 3.53(d, 1H), 4.63(d, 1H), 4.72(d, 1H), 7.24(m, 4H), J-10

S FROM 08/883,743 J-11 (S) Ph S (DMSO-d₆): δ 0.89(d, 3H), 0.91(d, 3H),1.81-1.98(m, 2H), 2.07-2.16(m, 1H), 2.31(d of ABX q, 1H), 2.54-2.63(m,3H), 4.96(s, 1H), 7.13-7.18(m, 3H), 7.23-7.28(m, 2H), 11.36(bs, 1H).J-11 (R) Ph R (DMSO-d₆) 0.89(d, 3H), 0.91 (d, 3H), 1.81-1.98(m, 2H),2.07-2.16(m, 1H), 2.31(d of ABX q, 1H), 2.55-2.63(m, 3H), 4.97(s, 1H),7.13-7.17(m, 3H), 7.23-7.28(m, 2H), 11.35(bs, 1H). J-12 (R)

R (DMSO-d₆) 0.87(d, 3H), 0.89(d, 3H), 1.81-1.93(m, 2H), 2.05-2.14(m,1H), 2.31(d of ABX q, 1H), 2.54-2.62(m, 3H), 4.95(s, 1H), 7.03-7.10(m,2H), 7.17-7.22(m, 2H). J-12 (S)

S (DMSO-d₆): δ 0.88 (d, 3H), 0.90(d, 3H), 1.82-1.92(m, 2H), 2.05-2.14(m,1H), 2.32(d of ABX q, 1H), 2.54-2.62(m, 3H), 4.96(s, 1H), 7.04-7.10(m,2H), 7.17-7.22(m, 2H). J-13

± MS(APCI): 295(M−H) J-14 (S)

S MS(APCI): 279(M−H) J-15 (S)

S (DMSO-d₆): δ 0.89(d, 3H), 0.91(d, 3H), 1.75-1.87(m, 2H),2.10-2.19(m+d, 4H), 2.69 (d, 1H), 2.58-2.65(m, 3H), 4.96(s, 1H),6.92-6.98(m, 2H), 7.08-7.15(m, 1H) J-16 (S)

S (DMSO-d₆) δ 0.87(d, 3H), 0.89(d, 3H), 1.87-1.93(m, 2H), 2.04-2.13(m,1H), 2.34(d, 1H), 2.54-2.65(m, 3H), 4.95 (s, 1H), 6.91-7.04(m, 3H). J-17(S)

S (DMSO-d₆) δ 0.89(d, 3H), 0.91(d, 3H), 1.73-1.85(m, 2H), 2.-08-2.17(m,1H), 2.20(s, 3H), 2.28(d, 1H), 2.49-2.65 (m, partially obscured by DMSO,3H), 4.95(s, 1H), 6.86-6.98(m, 2H), 7.07-7.12 (m, 1H).

[0870] The compounds of Table J above are named:

[0871] J-2:6-[2-(3-Fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one(R and S isomers);

[0872] J-3:6-[2-(3,4-Difluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one(R and S isomers);

[0873] J-4:4-Hydroxy-6-isopropyl-6-[2-(2-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-pyran-2-one;

[0874] J-5:4-Hydroxy-6-isopropyl-6-[2-(3-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-pyran-2-one;

[0875] J-6:4-Hydroxy-6-isopropyl-6-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-pyran-2-one;

[0876] J-7:6-[2-(3-Fluoro-5-trifluoromethyl-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0877] J-8:6-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0878] J-9:(S)-4-Hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0879] J-11:4-Hydroxy-6-isopropyl-6-(2-phenyl-ethyl)-5,6-dihydro-pyran-2-one (R andS isomers);

[0880] J-12:6-[2-(4-Fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one(R and S isomers);

[0881] J-13:4-Hydroxy-6-[2-(4-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[0882] J-14:(S)-4-Hydroxy-6-isopropyl-6-[2-(2-methyl-thiophen-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[0883] J-15:(S)-6-[2-(3-Fluoro-2-methyl-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[0884] J-16:(S)-6-[2-(3,5-Difluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;and

[0885] J-17:(S)-6-[2-(4-Fluoro-2-methyl-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one.

[0886] Synthesis of Tosylthiolate Side Chains

[0887] General Method 12. Preparation of Nitro Intermediates

[0888] The appropriate alkylbenzene (1 equiv.) was dissolved in aceticacid and acetic anhydride. To the solution was added sulfuric acid,followed by 70% nitric acid or fuming nitric acid (1 to 1.5 equiv.;ratio of concentrated sulfuric acid to nitric acid is 1:2), dropwise at0° C. After the addition, the reaction was warmed to room temperature.The reaction mixture was kept at room temperature to 80° C. for 6 to 18hours. The reaction mixture was poured into ice and extracted withEtOAc. The crude product was purified by either distillation or by flashsilica gel chromatography.

EXAMPLE K 1-Bromo-4-tert-butyl-2-nitro-benzene

[0889] The reaction was done as described in General Method 12 using1-bromo-4-tert-butyl-benzene (15 g), acetic acid (10 mL), nitric acid(6.5 g), and sulfuric acid (13 g). MS(APCI): 291.

[0890] General Method 13. Preparation of Benzthiazoles

[0891] To the aryl amine (1 equiv.) in MeOH or acetic acid was addedsodium or potassium or ammonium thiocyanate (3-6 equiv.). The reactionwas stirred at 0° C. to room temperature. This reaction mixture wascooled to 0° C. and treated dropwise with bromine (2-2.2 equiv.) or asolution of sodium bromide (2-2.2 equiv.) and bromine (2-2.2 equiv.).After the addition was complete, the reaction mixture was slowly warmedto room temperature and stirred at room temperature for 4 to 24 hours.The reaction mixture was added to sodium bicarbonate solution andextracted with EtOAc (2-4 times). The EtOAc layer was separated, washedwith H₂O and brine, and dried (MgSO₄). The organic layer wasconcentrated, and the residue was purified either by crystallization orby flash silica gel chromatography.

EXAMPLE L-1

[0892] 5-tert-Butyl-6-thiocyanato-benzothiazol-2-yl-amine

[0893] 1-Bromo-4-tert-butyl-2-nitro-benzene (18 g) was reduced asdescribed in General Method 3 using 10% palladium on charcoal (1 g) andMeOH (100 mL) in a hydrogen atmosphere (50 psi). The catalyst wasfiltered, and the solvents were evaporated. The residue was taken inEtOAc (100 mL) and washed with saturated sodium bicarbonate solution andH2O. The solution was dried and concentrated. The residue was purifiedby flash chromatography to give 3-tert-butyl-phenylamine. MS (APCI): 150(M+H).

[0894] The title compound was prepared according to General Method 13using 3-tert-butyl-phenylamine (9.4 g, 63 mmol), sodium thiocyanate(30.7 g, 379 mmol), sodium bromide (14.3 g, 139 mmol), bromine (22.2 g,139 mmol) and MeOH (300 mL). The crude reaction mixture was purified byflash chromatography (20% EtOAc in hexanes to 75% EtOAc in hexanes aseluents). MS (APCI): 264 (M+H).

EXAMPLE L-2

[0895] 5-iso-Propyl-6-thiocyanato-benzothiazol-2-yl-amine

[0896] The title compound was prepared according to General Method 13using 3-isopropyl-phenylamine (20.8 g, 154 mmol), sodium thiocyanate(74.8 g, 923 mmol), sodium bromide (34.8 g, 338 mmol), bromine (54.1 g,338 mmol), and MeOH (300 mL). The crude reaction mixture was purified byflash chromatography (CH₂Cl₂ to 25% EtOAc in CH₂Cl₂ as eluents). MS(APCI): 250 (M+H).

EXAMPLES L-3, L-4, and L-5

[0897] 2-Isopropyl-4-isothiocyanato-5-methyl-phenylamine,7-Isopropyl-4-methyl-6-thiocyanato-benzothiazol-2-yl-amine, and4-Isopropyl-7-methyl-6-thiocyanato-benzothiazol-2-yl-amine

[0898] The title compounds were prepared according to General Method 13using 2-isopropyl-5-methyl-phenylamine (contains approximately 10% of3-isopropyl-6-methyl-phenylamine) (20.0 g, 134 mmol), sodium thiocyanate(65.3 g, 805 mmol), sodium bromide (30.4 g, 295 mmol), bromine (47.2 g,295 mmol), and MeOH (300 mL). The crude reaction mixture was purified byflash chromatography (20% EtOAc in hexanes to 75% EtOAc in hexanes aseluents), which yielded three products:

[0899] L-3: 2-Isopropyl-4-isothiocyanato-5-methyl-phenylamine: uppermostspot on tic: MS (APCI): 207 (M+H).

[0900] L-4-4-Isopropyl-7-methyl-6-thiocyanato-benzothiazol-2-yl-amine:middle sport on tic: MS (APCI): 264 (M+H), 239.

[0901] L-5: 7-Isopropyl-4-methyl-6-thiocyanato-benzothiazol-2-yl-amine:lowest spot on tic: MS (APCI): 264 (M+H)

EXAMPLE L-6

[0902] 6-tert-Butyl-4-thiocyanato-benzothiazol-2-yl-amine

[0903] The title compound was prepared according to General Method 13using 4-tert-butyl-phenylamine (16.2 g, 109 mmol), sodium thiocyanate(53.0 g, 653 mmol), sodium bromide (24.6 g, 240 mmol), bromine (38.3 g,240 mmol), and MeOH (300 mL). The crude product was purified by silicagel chromatography (10-50% EtOAc in hexanes as eluents). MS (APCI): 263(M).

[0904] General Method 14. Cleavage of SCN Group

[0905] A solution of the SCN intermediate in denatured EtOH was treatedwith dithiothreitol (3-5 equiv.) and 0.2 M KH₂PO₄ (in a ratio of 4:1EtOH:buffer). The mixture was stirred for 6 to 48 hours at 0° C. to 50°C. The solvent was evaporated, and H₂O and CHCl₃ were added; the organiclayer was washed with brine, dried (Na₂SO₄), filtered and concentrated.The resulting residue was flash chromatographed on silica gel.

[0906] General Method 14b. Alternate Cleavage of the SCN Group

[0907] The thiocyante (1 eq.) was dissolved in THF and treated withsodium hydrogen sulfide (3 eq.) and sodium borohydride (6 eq.). Amixture of MeOH and water (2:1) was added dropwise at 0° C., and thereaction mixture was stirred at room temperature overnight. Water andtoluene were added, and the reaction was quenched with glacial aceticacid at 0° C. The organic layer was separated, washed with H₂O, anddried (MgSO₄.) The organic layer was concentrated, and the crude wasused without any purification.

EXAMPLE M-1

[0908] 2-Amino-5-tert-butyl-benzothiazole-6-thiol

[0909] The title compound was prepared according to General Method 14using 5-tert-butyl-6-thiocyanato-benzothiazol-2-yl-amine (Example L-1; 8g, 30 mmol), dithiothreitol (18.7 g, 121 mmol), EtOH (200 mL), andphosphate buffer (50 mL). MS (APCI): 239 (M+H).

EXAMPLE M-2

[0910] 2-Amino-5-isopropyl-benzothiazole-6-thiol and5-Isopropyl-benzothiazole-6-thiol

[0911] The title compound was prepared according to General Method 14using 5-isopropyl-6-thiocyanato-benzothiazol-2-yl-amine (Example L-2;23.5 g, 94.4 mmol), dithiothreitol (58.2 g, 377 mmol), EtOH (300 mL),and phosphate buffer (150 mL). The reaction mixture was kept underreflux overnight. The reaction mixture contained a mixture of2-amino-5-isopropyl-benzothiazole-6-thiol and5-isopropyl-benzothiazole-6-thiol in 1:2 ratio. The crude reactionmixture was used as such without any further purification.2-Amino-5-isopropyl-benzothiazole-6-thiol: MS (APCI): 225 (M+H);5-Isopropyl-benzothiazole-6-thiol: MS (APCI): 210 (M+H).

EXAMPLE M-3

[0912] 2-Amino-7-isopropyl-4-methyl-benzothiazole-6-thiol

[0913] The title compound was prepared according to General Method 14using 7-isopropyl-4-methyl-6-thiocyanato-benzothiazol-2-yl-amine(Example L-5; 11.5 g, 43.7 mmol), dithiothreitol (27.0 g, 175 mmol),EtOH (200 mL), and phosphate buffer (50 mL). MS (APCI): 239 (M+H).

EXAMPLE M-4

[0914] 2-Amino-6-tert-butyl-benzothiazole-4-thiol

[0915] The title compound was prepared according to General Method 14using 6-tert-butyl-4-thiocyanato-benzothiazol-2-yl-amine (Example L-6;2.0 g. 7.6 mmol), dithiothreitol (4.6 g, 30 mmol), phosphate buffer ofpH 7 (10 mL), and EtOH (50 mL). The crude product was used furtherwithout any purification. MS (APCI): 239 (M+H).

EXAMPLE N

[0916]2-(Methyloxycarbonyl)amino-4-isopropyl-7-methyl-benzothiazole-6-thiol

[0917] To 4-isopropyl-7-methyl-6-thiocyanato-benzothiazol-2-yl-amine(Example L-4; 4.0 g, 17 mmol) dissolved in CH₂Cl₂ (25 mL) and pyridine(5 mL), was added methyl chloroformate at 0° C. The reaction mixture wasstirred at room temperature for 2 hours. H₂O was added to the reactionmixture followed by EtOAc (100 mL). The organic layer was washed with 2NHCl, H₂O, saturated sodium bicarbonate solution and brine, and was dried(MgSO₄). The solvents were evaporated, and the residue was purified byflash chromatography (100% hexanes to 25% EtOAc in hexanes) to give2-(methyloxycarbonyl)amino-4-isopropyl-7-methyl-6-thiocyanato-benzothiazole.MS (APCI): 322 (M+H).

[0918] The title compound was prepared according to General Method 14using2-(methyloxycarbonyl)amino-4-isopropyl-7-methyl-6-thiocyanato-benzothiazole(1.5 g, 4.7 mmol), dithiothreitol (2.9 g, 18.7 mmol), EtOH (50 mL), andphosphate buffer (15 mL). MS (APCI): 296 (M−H).

[0919] Preparation of Benzothiphenes

EXAMPLE O

[0920] 3-tert-Butyl-2-mercapto-benzo[b]thiophene

[0921] A solution of 3-tert-butylbenzo[b]thiophene (2.00 g, 10.4 mmol;J. Chem. Soc., Perkin Trans. 1, 1972;3:414-18) in Et₂O (30 mL, N₂atmosphere) was treated with a 1.6 M hexane solution of nBuLi (3.75 mL,12 mmol) and allowed to stir overnight. The mixture was then cooled to0° C. and treated with dry precipitated sulfur (0.38 g, 12 mmol). Themixture was allowed to stir for 2 hours, then quenched with ice H₂O. Themixture was washed with Et₂O, and the aqueous layer was acidified with 1N HCl and extracted with Et₂O. The organic layers were combined, dried(MgSO₄), and concentrated. The crude thiol was used without purificationin the next step.

EXAMPLE P

[0922] 2-(3,5-Dibromo-thiophen-2-yl)-propan-2-ol

[0923] A solution of 2,3,5-tribromothiophene (8.17 g, 25 mmol) in Et₂O(N₂ atmosphere) was cooled to −78° C. and treated with a 1.6 M hexanesolution of nBuLi (15.6 mL, 25 mmol). The mixture was then stirred for10 minutes, then treated with acetone (1.84 mL, 25 mmol). The mixturewas then stirred for 30 minutes and quenched with H₂O. The mixture wasextracted with Et₂O; the organic layers were combined, dried (MgSO₄),and the solvent removed in vacuo. The residue was filtered through aplug of silica gel (gradient elution from hexanes to EtOAc) to providethe title compound.

[0924]¹H NMR (CDCl₃): δ 1.70 (s, 6H), 2.40 (br s, 1H), 6.89 (s, 1H).

EXAMPLE Q

[0925] (4-Bromo-5-isopropyl-thiophen-2-yl)-methanol

[0926] A solution of 2-(3,5-dibromo-thiophen-2-yl)-propan-2-ol (ExampleP; 7.64 g, 25 mmol) in CH₂Cl₂ (100 mL) was cooled to 0° C. and treatedwith triethylsilane (6.80 mL, 30.56 mmol) followed by triflouroaceticacid (40 mL). The mixture was stirred for 15 minutes and thenconcentrated in vacuo. The residue was taken up in hexanes and filteredthrough a plug of silica gel. The solvent was removed in vacuo, and theresidue was diluted with Et₂O and cooled to −78° C. (N2 atmosphere). Themixture was treated with a 1.6 M hexane solution of nBuLi (15.6 mL, 25mmol), stirred 10 minutes, and treated with a solution of4-formylmorpholine (2.88 mL, 25 mmol) in Et₂O (25 mL). The mixture wasallowed to slowly come to room temperature overnight, then quenched withH₂O and extracted with Et₂O. The organic layers were combined, dried(MgSO₄), and concentrated.

[0927] The residue was then taken up in MeOH (250 mL) and treated withan excess of sodium borohydride. After 30 minutes, the mixture wasdiluted with Et₂O, washed with H₂O, and dried (MgSO₄). The solvent wasevaporated and the residue purified via silica gel chromatography(hexanes to 10% EtOAc:hexanes) to provide the title compound.

[0928]¹H NMR (CDCl₃): δ 1.28 (d, 6H), 1.73 (bs, 1H), 3.31 (sept, 1H),4.73 (d, 2H), 6.82 (d, 1H).

EXAMPLE R

[0929](4-Bromo-5-isopropyl-thiophen-2-yl-methoxy)-tert-butyl-dimethyl-silane

[0930] A solution of (4-bromo-5-isopropyl-thiophen-2-yl)-methanol(Example Q; 3.4 g, 14 mmol) in CH₂Cl₂ (4.0 mL) was treated with NEt₃(2.8 mL, 20 mmol), p-dimethylaminopyridine (0.050 g), andt-butyldimethylsilylchloride (2.41 g, 16.0 mmol). The mixture wasstirred for 14 hours, then diluted with Et₉O and washed with H₂O. Theorganic layer was dried (MgSO₄) and the solvent evaporated to providethe crude product, which was used without further purification.

[0931]¹H NMR (CDCl₃): δ 0.0 (s, 6H), 0.82 (s, 9H), 1.17 (d, 6H), 3.20(sept, 1H), 4.66 (d, 2H), 6.60 (s, 1H).

EXAMPLE S

[0932]5-(tert-Butyl-dimethyl-silanyloxymethyl)-2-isopropyl-3-mercapto-thiophene

[0933] A solution of(4-bromo-5-isopropyl-thiophen-2-ylmethoxy)-tert-butyl-dimethyl-silane(Example R; 4.7 g, 13.5 mmol) in Et₂O (100 mL, N₂ atmosphere) was cooledto −78° C. and treated with a 1.6 M hexane solution of nBuLi (8.42 mL,13.5 mmol). After 10 minutes, dry triturated sulfur (0.43 g, 13.5 mmol)was added, and the mixture was allowed to warm to room temperature.After 2 hours the mixture was diluted with Et₂O and washed with 0.5 MHCl. The organic layer was dried (MgSO₄) and concentrated to give thetitle compound, which was used crude in the next step.

EXAMPLE T

[0934] 5-tert-Butyl-4-hydroxy-2-methylbenzaldehyde

[0935] Aluminum chloride (26.6 g, 200 mmol) was added to chlorobenzene(40 mL), and the mixture was cooled to −10° C. A solution of2-tert-butyl-5-methylphenol (16.4 g, 100 mmol) in triethyl orthoformate(32.5 g, 220 mmol) was added dropwise. When addition was complete, thereaction mixture was warmed to 0° C. to 5° C. and kept at thattemperature for 6 hours. Five percent HCl (100 mL) was added, and themixture was extracted with 1:1 EtOAC:toluene. The organic phase wasextracted with 23% KOH (3×50 mL) and water (25 mL), and the waterextract was combined with the KOH extracts. The pH of the combinedaqueous extracts was adjusted to 4 with 37% HCl. The resultingprecipitate was filtered, washed with water (3×50 mL), and dried to givethe title compound, mp 171-171° C.

EXAMPLE U

[0936] Dimethylthiocarbamic acidO-(2-tert-butyl-4-formyl-5-methylphenyl) Ester

[0937] Ten percent KOH (80 mL) was added to a mixture of5-tert-butyl-4-hydroxy-2-methylbenzaldehyde (Example T; 99.0 g, 515mmol) in water (180 mL) and THF (135 mL.) The mixture was treated with asolution of N,N-dimethylthiocarbamoyl chloride (86.1 g) in THF (108 mL)over a 2-hour period with simultaneous addition of 10% KOH in order tohold the pH of the reaction mixture between 12.0 and 12.3. Afterapproximately 70% of the dimethylthiocarbamoyl chloride-THF solution hadbeen added, vacuum was applied to the reaction mixture to remove theTHF; during this distillation, the simultaneous additions of 10% KOH andthe dimethylthiocarbamoyl chloride-THF solution were continued whilemaintaining the pH range between 12.0 and 11.6 and the reactiontemperature between 23° C. to 25° C. The distillation was continued for10 minutes after all the dimethylthiocarbamoyl chloride solution hadbeen added. Stirring at ambient pressure and temperature was continuedfor another 90 minutes, during which time the pH was stable between 11.6and 11.75. A solution of EtOAc (150 mL) and heptane (150 mL) was addedto the reaction mixture, and after stirring and settling, the layerswere separated and the aqueous layer extracted with 1:1 heptane:EtOAc.The combined organic extracts were extracted with 10% KOH (2×100 mL) andwater (2×90 mL) and concentrated. The residue was diluted with MeOH (120mL). The solution was warmed to 45° C. and H₂O (20 mL) was added. Thesolution was cooled to room temperature, 50% NaOH (170 mg) was added,and the solution was concentrated. This residue was redissolved in MeOH(120 mL) at 50° C. and H₂O (15 mL) was added. The solution was cooledslowly to −5° C. with the addition of dimethylthiocarbamic acidO-(2-tert-butyl-4-formyl-5-methyl-phenyl) ester seed crystals to promotecrystallization. The mixture was filtered and the solid washed with 4:1MeOH:H₂O to give the title compound, mp 80-81° C.

EXAMPLE V

[0938] (5-tert-Butyl-4-mercapto-5-methyl-phenyl)methanol

[0939] Dimethylthiocarbamic acidO-(2-tert-butyl-4-formyl-5-methylphenyl) ester (Example U; 24.0 g, 85.9mmol) was treated with tetraethylene glycol dimethyl ether (65 g), andthe mixture was stirred and heated under argon to 275° C. The solutionwas heated at this temperature for 30 minutes. The solution was cooled,and H₂O was added. The mixture was cooled to 0° C. and filtered; thesolid was washed with H₂O to give dimethyl thiocarbamic acidS-(2-tert-butyl-4-formyl-5-methyl-phenyl) ester.

[0940] The crude solid was treated with MeOH (40 mL) and THF (30 mL)followed by slow addition (20 minutes) of NaBH₄ (14.1 g of a 12 weightpercent solution in 14 M NaOH), while maintaining the temperature below8° C. The resulting solution was stirred at 20° C. to 25° C. for 90minutes. Fifty percent NaOH (4 g) was added, and the solution was heatedto reflux for 3 hours. The mixture was cooled to room temperature,treated with H₂O (110 mL) and toluene (70 mL), and acidified to pH 4with 37% HCl. The aqueous layer was separated and extracted with toluene(2×15 mL). Concentration gave the title compound which was used withoutfurther purification in the next step.

EXAMPLE W

[0941] 3-tert-Butyl-4-dimethylcarbamoylsulfanyl-benzoic acid methylEster

[0942] A solution of 3.0 g (14.4 mmol) of 3-tert-butyl-4-hydroxy-benzoicacid methyl ester (Aust. J. Chem., 1978;31:907-916), cesium carbonate(7.04 g, 21.6 mmol), and acetonitrile (50 mL) was heated to reflux andthen treated with N,N-dimethylthiocarbamoyl chloride (2.67 g, 21.6 mmol)all at once. The mixture was refluxed for 2 hours, cooled to roomtemperature, and quenched with 1N HCl. The solution was extracted withEtOAc; the organic layer was washed with 1N NaOH and brine, dried(MgSO₄), and concentrated. The residue was chromatographed over silicagel, eluting with 3:2 hexane:EtOAc, to give3-tert-butyl-4-dimethylthiocarbamoyloxy-benzoic acid methyl ester.

[0943]¹H NMR (CDCl₃): δ 1.39 (s, 9H), 3.44 (d, 6H), 3.90 (s, 3H), 7.09(d, 1H), 7.89 (dd, 1H), 8.12 (m, 1H).

[0944] Neat 3-tert-butyl-4-dimethylthiocarbamoyloxy-benzoic acid methylester (2.71 g, 9.2 mmol) was heated to 230° C. for 2 hours and thencooled to room temperature. The material was chromatographed over silicagel, eluting with 7:3 hexane:EtOAc, to give the title compound.

[0945]¹H NMR (CDCl₃): δ 1.50 (s, 9H), 3.11 (br s, 6H), 3.91 (s, 3H),7.53 (d, 1H), 7.84 (dd, 1H), 8.13 (d, 1H).

EXAMPLE X

[0946] (3-tert-Butyl-4-mercapto-phenyl)methanol

[0947] A solution of 2.1 g (7.1 mmol) of3-tert-butyl-4-dimethylcarbamoylsulfanyl-benzoic acid methyl ester(Example W) in toluene (100 mL) was cooled to −78° C. and treated with42 mL of DIBAL (1.0 M in CH₂Cl₂; 42 mmol). The reaction mixture wasallowed to warm to room temperature overnight. The reaction was quenchedcautiously with saturated aqueous citric acid and extracted with EtOAc(2×100 mL). The combined organic extracts were washed with brine, dried(MgSO₄), and concentrated. Chromatography of the residue over silicagel, eluting with 3:2 hexane:EtOAc, gave the title compound.

[0948]¹H NMR (CDCl₃): δ 1.48 (s. 9H), 1.97 (br s, 1H). 3.61 (s, 1H),4.59 (s, 2H), 7.02 (dd, 1H), 7.20 (d, 1H), 7.34 (d, 1H).

EXAMPLE Y

[0949] (5-tert-Butyl-4-hydroxy-2-methyl-phenyl)-acetic Acid, MethylEster

[0950] A solution of 8.5 g (51 mmol) of(4-hydroxy-2-methyl-phenyl)-acetic acid (Indian J. Chem. Sect. B. 26,1987:679-682), tert-butanol (60 g), and conc, sulfuric acid (2 mL) wasstirred at 70° C. for 5 days. The solution was cooled to roomtemperature, poured into water, and extracted with EtOAc. The organicextract was washed with brine, dried (MgSO₄), and concentrated to give(5-tert-butyl-4-hydroxy-2-methyl-phenyl)-acetic acid.

[0951]¹H NMR (CDCl₃): δ 1.33 (s, 9H), 2.14 (s, 3H), 3.54 (s, 2H), 6.47(s, 1H), 7.00 (s, 1H).

[0952] A mixture of the (5-tert-butyl-4-hydroxy-2-methyl-phenyl)-aceticacid isolated above (11.3 g, 51 mmol), MeOH (150 mL), and conc. sulfuricacid (2 mL) was refluxed overnight. The solution was cooled to roomtemperature and concentrated. The residue was partitioned between EtOAcand water; the organic phase was washed with brine, dried (MgSO₄), andconcentrated. The product was chromatographed over silica gel, elutingwith hexane:EtOAc, to give the title compound.

[0953]¹H NMR (CDCl₃): δ 1.35 (s, 9H), 2.16 (s, 3H), 3.54 (s, 2H), 3.67(s, 3H), 6.46 (s, 1H), 7.01 (s, 1H).

EXAMPLE Z

[0954] (5-tert-Butyl-4-dimethylcarbamoylsulfanyl-2-methyl-phenyl)-aceticAcid Methyl Ester

[0955] A solution of 3.0 g (13 mmol) of(5-tert-butyl-4-hydroxy-2-methyl)-phenyl acetic acid, methyl ester(Example Y) in 20 mL of DMF was treated portionwise with 0.60 g (15mmol) of NaH and stirred at room temperature for 1 hour.N,N-dimethylthiocarbamoyl chloride (2.35 g, 19 mmol) was added all atonce, and the reaction mixture was stirred at 70° C. overnight. Waterwas added: the solution was extracted with EtOAc. The organic layer wasseparated, washed with brine, dried (MgSO₄), and concentrated. The crudematerial was chromatographed over silica gel, eluting with hexane:EtOAc3:1, to give(5-tert-butyl-4-dimethylthiocarbamoyloxy-2-methyl-phenyl)-acetic acidmethyl ester.

[0956]¹H NMR (CDCl₃): δ 1.30 (s, 9H), 2.22 (s, 3H), 3.40 (d, 6H), 3.58(s, 2H), 3.66 (s, 3H), 6.80 (s, 1H), 7.17 (s, 1H).

[0957] The product isolated above (2.1 g, 6.5 mmol) was heated neat to310° C. for 1 hour and then cooled to room temperature. The residue waschromatographed on silica gel, eluting with hexane:EtOAc 2: 1, to givethe title compound.

[0958]¹H NMR (CDCl₃): δ 1.41 (s, 9H), 2.22 (s, 3H), 3.00-3.10 (br d,6H), 3.58 (s, 2H), 3.65 (s, 3H), 7.22-7.24 (m, 2H).

EXAMPLE AA

[0959] 2-(5-tert-Butyl-4-mercapto-2-methyl-phenyl)-ethanol

[0960] A solution of 0.68 g (2.1 mmol) of(5-tert-butyl-4-dimethylcarbamoylsulfanyl-2-methyl-phenyl)-acetic acidmethyl ester (Example Z) in 20 mL of toluene was cooled to −78° C. andtreated dropwise with 1.0 M DIBAL in CH₂Cl₂ (10 mL; 10 mmol). The coldbath was removed, and the mixture was stirred at room temperature for 2hours. Saturated citric acid was added cautiously. H₂O and EtOAc wereadded, and the mixture was filtered. The filtrate was transferred to aseparatory funnel where the aqueous phase was isolated and re-extractedwith EtOAc. The organic extracts were combined, washed with brine, anddried (MgSO₄). Concentration gave an oil which was chromatographed oversilica gel, eluting with 1:1 hexane:EtOAc, to give the title compound.

[0961]¹H NMR (CDCl₃): δ 1.42 (s, 9H), 2.20 (s, 3H), 2.79 (t, 2H), 3.49(t, 1H), 3.76 (t, 2H), 7.01 (s, 1H), 7.11 (s, 1H).

[0962] General Method 15. Preparation of Tosyl Reagents

[0963] A solution of p-toluenesulfonyl bromide (1 equiv.), a base suchas NEt₃ or pyridine (1-1.5 equiv.), and a solvent such as CCl₄ or EtOAcat 0° C. to 24° C. was treated with a solution of the appropriate thiol(1 equiv.) in CCl₄ or EtOAc in a dropwise fashion. Addition was completein 0.5 to 11 hours. The reaction was allowed to warm to roomtemperature. H₂O was added; the organic layer was separated, washed withsaturated aqueous NH₄Cl and brine, and dried (MgSO₄). Concentration gavea residue which could be purified either by silica gel chromatography orby trituration.

EXAMPLE BB-1

[0964] Toluene-4-thiosulfonic acidS-(2-amino-5-tert-butyl-benzothiazol-6-yl)ester

[0965] The title compound was prepared according to General Method 15using 2-amino-5-tert-butyl-benzothiazole-6-thiol (7.0 g, 29 mmol),pyridine (2.3 g, 29 mmol), tosyl bromide (6.9 g, 29 mmol), carbontetrachloride (100 mL), and EtOAc (100 mL). The crude reaction mixturewas purified by flash chromatography (5% EtOAc in hexanes to 50% EtOAcin hexanes as eluents). MS(APCI): 393 (M+H).

EXAMPLE BB-2

[0966] Toluene-4-thiosulfonic aidS-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl) Ester

[0967] A solution of (5-tert-butyl-4-mercapto-5-methyl-phenyl)methanol(from Example V), pyridine (6.12 G), and toluene (30 mL) was slowlyadded (over 3 hours) at 40° C. to a prestirred solution oftoluenesulfonyl chloride (16.6 g) and lithium bromide (8.0 g) in THF (75mL). The resulting mixture was stirred at 40° C. for 2 hours and thenovernight at room temperature. H₂O (70 mL) and EtOAc (30 mL) were added.The organic layer was separated and washed with 10% HCl (2×50 mL) andH₂O (50 mL). The solution was concentrated to give a residue which waswarmed to 60° C. and treated with heptane. This solution was stirred andcooled to 10° C.; the solids were filtered and washed with 1:1toluene:heptane. Upon drying in vacuo, the title compound was obtained,mp 121-122° C.

[0968] The following tosylthiolates were prepared using the appropriatethiol and following General Method 15: TABLE K Thiotosylate Side ChainsPrep. of Starting Materials Example Structure ¹H NMR or MS Data ExamplesL-2 and M-2 BB-3

MS(APCI): 378 Examples L-2 and M-2 BB-4

MS(APCI): 364(M+H) Examples L-5 and M-3 BB-5

MS(APCI): 393(M+H) Examples L-4 and N BB-6

MS(APCI): 451(M+H) Examples L-6 and M-4 BB-7

MS(APCI): 393(M+H) Example O BB-8

(CDCl₃): δ 1.54(s, 9H), 2.43(s, 3H), 7.24(d, 2H), 7.32-7.39(m, 2H),7.62(d, 2H), 7.69-7.75(m, 1H), 8.17-8.21(m, 1H). Example P-S BB-9

(CDCl₃): δ 0.00(s, 6H), 0.82(s, 9H), 0.91(d, 6H), 2.31(s, 3H),2.93(sept., 1H), 4.65(d, 2H), 6.60(s, 1H), 7.13(d, 2H), 7.41(d, 2H).BB-10

USSM 08/883,743 BB-11

USSN 08/883,743 BB-12

USSN 08/883,743 Examples W and X BB-13

(CDCl₃): δ 1.23(s, 9H), 2.40(s, 3H), 4.73(s, 2H), 7.23(m, 3H), 7.43(m,1H), 7.46-7.50(m, 2H), 7.61(d, 1H). Examples Y, Z and AA BB-14

(CDCl₃): δ 1.21(s, 9H), 2.17(s, 3H), 2.39(s, 3H), 2.85(t, 2H), 3.80(t,2H), 7.18-7.22(m, 4H), 7.47(d, 2H). Example BB-11 BB-15

Examples CC-FF BB-16

(CDCl₃): δ 1.28(s, 9H), 1.69(s, 9H), 2.4(s, 3H), 6.5(d, 1H), 7.2 (d,2H), 7.44(d, 2H), 7.61(d, 1H), 7.81(s, 1H), 8.28(br s, 1H). ExamplesGG-LL BB-17

MS(APCI): 462 (M+H) Examples MM-NN BB-18

(CDCl₃): δ 1.22(s, 9H), 2.44(s, 3H), 2.99(t, 2H), 4.03(t, 2H), 7.22(d,2H), 7.39(d, 2H), 7.42(s, 1H), 7.66(s, 1H), 7.81(d, 2H), 7.94 (d, 2H).Examples OO-1-VV-1 BB-19

MS(APCI): 347 (M+H). Examples OO-2-VV-2 BB-20

MS(APCI): 361 (M+H). Examples OO-2-VV-2 BB-21

MS(APCI): 375 (M−H). Examples WW-AAA BB-22

MS(APCI): 432 (M+H) Examples BBB-DDD BB-23

MS(APCI): 405 (M+H) Example BB-1 BB-24

MS(APCI): 558 (M+H) Example BB-1 BB-25

MS(APCI): 471 (M+H) Example BB-1 BB-26

MS(APCI): 435 (M+H) Example VV-1 BB-27

MS(APCI): 363 (M+H)

[0969] The compounds from Table K above are named:

[0970] BB-3: Toluene-4-thiosulfonic acidS-(2-amino-5-isopropyl-benzothiazol-6-yl)ester;

[0971] BB-4: Toluene-4-thiosulfonic acidS-(5-isopropyl-benzothiazol-6-yl)ester;

[0972] BB-5: Toluene-4-thiosulfonic acidS-(2-amino-7-isopropyl-4-methyl-benzothiazol-6-yl)ester;

[0973] BB-6: Toluene-4-thiosulfonic acidS-(4-isopropyl-2-methoxycarbonylamino-7-methyl-benzothiazol-6-yl)ester;

[0974] BB-7: Toluene-4-thiosulfonic acidS-(2-amino-6-tert-butyl-benzothiazol-4-yl)ester;

[0975] BB-8: Toluene-4-thiosulfonic acidS-(3-tert-butyl-benzo[b]thiophen-2-yl)ester;

[0976] BB-9: Toluene-4-thiosulfonic acidS-[5-(tert-butyl-silanyloxymethyl)-2-isopropyl-thiophen-3-yl] ester;

[0977] 15 BB-13: Toluene-4-thiosulfonic acidS-(2-tert-butyl-4-hydroxymethyl-phenyl)ester;

[0978] BB-14: Toluene-4-thiosulfonic acidS-[2-tert-butyl-4-(2-hydroxy-ethyl)-5-methyl-phenyl]ester; and

[0979] BB-15: Benzenesulfonothioic acid, 4-methyl-,S-[2-(1,1-dimethylethyl)-5-methyl-4-[[[[(5-trifluoromethyl)-2-pyridinyl]sulfonyl]amino]phenyl]ester;

[0980] BB-16:6-tert-Butyl-5-(toluene-4-sulfonylsulfanyl)-indole-1-carboxylic acidtert-butyl ester;

[0981] BB-17:6-tert-Butyl-5-(toluene-4-sulfonylsulfanyl)-2,3-dihydro-indole-1-carboxylicacid tert-butyl ester;

[0982] BB-18: Toluene-4-thiosulfonic acidS-[6-tert-butyl-1-(4-cyanobenzenesulfonyl)-2,3-dihydro-1H-indol-5-yl]ester;

[0983] BB-19: Toluene-4-thiosulfonic acidS-(6-isopropyl-3H-benzoimidazol-5-yl) ester;

[0984] BB-20: Toluene-4-thiosulfonic acidS-(6-tert-butyl-3H-benzoimidzol-5-yl) ester;

[0985] BB-21: Toluene-4-thiosulfonic acidS-(6-tert-butyl-2-oxo-2,3-dihydro-1H-benz-oimidzol-5-yl) ester;

[0986] BB-22:6-tert-Butyl-5-(toluene-4-sulfonylsulfanyl)-1H-indole-2-carboxylic acidethyl ester;

[0987] BB-23: Toluene-4-thiosulfonic acidS-(7-tert-butyl-2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-6-yl) ester;

[0988] BB-24: Toluene-4-thiosulfonic acidS-[5-tert-butyl-2-(4-cyanobenzenesulfonyl-amino)-benzothiazol-6-yl)]ester;

[0989] BB-25: Toluene-4-thiosulfonic acidS-(6-tert-butyl-2-methanesulfonylamino-benzothiazol-6-yl) ester;

[0990] BB-26: Toluene-4-thiosulfonic acidS-(2-acetylamino-5-tert-butyl-benzothiazol-6-yl) ester; and

[0991] BB-27: Toluene-4-thiosulfonic acidS-(6-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) ester.

EXAMPLE BB-15

[0992] Benzenesulfonothioic acid, 4-methyl-,S-[2-(1,1-dimethylethyl)-5-methyl-4-[[[[(5-trifluoromethyl)-2-pyridinyl]sulfonyl]amino]phenyl]ester

[0993] Compound BB-11(0.5 g, 1.43 mmol) was dissolved in pyridine (5 mL)and CH₂Cl₂ (2 mL). To this solution was added 0.53 g (2.16 mmol) of5-(trifluoromethyl)pyridine-2-sulfonyl chloride (J. Amer. Chem. Soc.,1997;119(15):3627-3628), and the reaction mixture was stirred under N₂at room temperature overnight. 1N HCl was then added; the mixture wasextracted with EtOAc, washed with 1 N HCl and brine, dried (MgSO₄),filtered, and concentrated. The resulting residue was chromatographedover silica gel, eluting with 9:1 CH₂Cl₂:EtOAc to afford the desiredproduct.

[0994]¹H NMR (CDCl₃): δ 1.13 (s, 9H), 2.19 (s, 3H), 2.42 (s, 3H), 6.83(s, 1H), 7.22 (d, 2H), 7.40 (s, 1H) 7.45 (d, 2H), 8.08 (d, 1H), 8.15 (m,1H), 8.99 (s, 1H).

EXAMPLE BB-24

[0995] Toluene-4-thiosulfonic acidS-[5-tert-butyl-2-(4-cyanobenzenesulfonyl-amino)-benzothiazol-6-yl)]Ester

[0996] The title compound was prepared as described in Example BB-15using toluene-4-thiosulfonic acidS-(2-amino-5-tert-butyl-benzothiazol-6-yl)ester (prepared in ExampleBB-1; 1.0 g, 3.37 mmol), 4-cyanobenzenesulfonyl chloride (0.68 g, 3.37mmol), pyridine (10 mL) and CH₂Cl₂ (3 mL). The crude product waspurified by flash silica gel chromatography (20%-70% EtOAc in hexanes aseluents). MS(APCI): 558 (M+H).

EXAMPLE BB-25

[0997] Toluene-4-thiosulfonic acidS-(6-tert-butyl-2-methanesulnoylamino-benzothiazol-6yl) Ester

[0998] The title compound was prepared as described in Example BB-15using toluene-4-thiosulfonic acidS-(2-amino-5-tert-butyl-benzothiazol-6-yl)ester (prepared in ExampleBB-1; 1.75 g, 4.47 mmol), methanesulfonyl chloride (1.02 g, 8.94 mmol),pyridine (3 mL), DMAP (0.3 g) and CH₂Cl₂ (20 mL). The crude product waspurified by flash silica gel chromatography (20%-70% EtOAc in hexanes aseluents). MS(APCI): 471 (M+H).

EXAMPLE BB-26

[0999] Toluene-4-thiosulfonic acidS-(2-acetylamino-5-tert-butyl-benzothiazol-6-yl) Ester

[1000] The title compound was prepared as described in Example BB-15using toluene-4-thiosulfonic acidS-(2-amino-5-tert-butyl-benzothiazol-6-yl)ester (prepared in ExampleBB-1; 1.75 g, 4.47 mmol), acetyl chloride (4 mL), pyridine (5 mL), DMAP(0.3 g) and CH₂Cl₂ (20 mL). The crude product was purified by flashsilica gel chromatography (20%-70% EtOAc in hexanes as eluents).MS(APCI): 435 (M+H).

EXAMPLE BB-27

[1001] Toluene-4-thiosulfonic acidS-(6-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) Ester

[1002] Toluene-4-thiosulfonic acidS-(1,2-diamino-5-isopropyl-phenyl)ester (prepared in Example VV-1 below;0.5 g, 1.5 mmol) and triphosgene (0.15 g, 0.5 mmol) were dissolved inTHF (30 mL). NEt₃ (1 mL) was added, and the reaction mixture was stirredat 90° C. for 1.5 hours. The crude reaction mixture was subjected toflash silica gel chromatography (EtOAc to 2%-10% MeOH in CH₂Cl₂ aseluents). MS(APCI): 363 (M+H).

EXAMPLE CC

[1003] (5-tert-Butyl-2-methyl-phenyl)-carbamic Acid Tert-Butyl Ester

[1004] 5-tert-Butyl-2-methyl-phenylamine (50 g, 307 mmol) in 500 mL ofhexanes was treated with di-t-butyl dicarbonate (80.3 g, 368 mmol.). Thereaction mixture was kept under reflux overnight. After cooling to roomtemperature, the reaction mixture was diluted with EtOAc, washed withsaturated NaHCO₃ solution and brine, and dried (MgSO₄). Afterevaporation of the solvents, the crude reaction mixture was purified byflash silica gel chromatography to give the title compound. MS(APCI):262 (M−H).

EXAMPLE DD

[1005] (5-tert-Butyl-2-methyl-4-thiocyanto-phenyl)-carbamic AcidTert-Butyl Ester

[1006] Thiocyanation was performed as described in the General Method 13using (5-tert-butyl-2-methyl-phenyl)-carbamic acid tert-butyl ester(prepared in Example CC; 4.32 g, 15.82 mmol), sodium thiocyanate (7.7 g,94.95 mmol), sodium bromide (1.95 g, 18.98 mmol), bromine (3.03 g, 18.98mmol), and methanol (50 mL). MS(APCI): (M+H).

EXAMPLE EE

[1007] (5-tert-Butyl-4-mercapto-2-methyl-phenyl)-carbamic AcidTert-Butyl Ester

[1008] The title compound was prepared according to General Method 14using (5-tert-butyl-2-methyl-4-thiocyanto-phenyl)-carbamic acidtert-butyl ester (prepared in Example DD; 30 g, 93.75 mmol),dithiothreitol (29 g, 187.5 mmol) and phosphate buffer (50 mL).MS(APCI): 294 (M−H).

EXAMPLE FF

[1009] 6-tert-Butyl-5-mercapto-indole-1-carboxylic Acid Tert-Butyl Ester

[1010] (5-tert-Butyl-4-mercapto-2-methyl-phenyl)-carbamic acidtert-butyl ester (prepared in Example EE; 20 g, 68 mmol) was dissolvedin 100 mL of THF, cooled to −40° C., and treated dropwise withsec-butyllithium (1.3 M, 156 mL, 203 mmol). After the addition wascomplete, the reaction mixture was stirred at −30° C. to −45° C. for 30minutes. To the mixture was added DMF (14.8 g, 203.39 mmol), and thesolution was stirred at −35° C. for 30 minutes. The reaction mixture wasslowly warmed to room temperature and was quenched with saturated NH₄Clsolution. EtOAc (200 mL) was added; the organic layer was washed withbrine, dried (MgSO₄) and concentrated. The residue was dissolved in 100mL of THF and 2 mL of concentrated HCl and stirred at room temperaturefor 1 hour. The solution was diluted with EtOAc, washed with NaHCO₃solution and brine, and dried (MgSO₄). The crude product was purified byflash silica gel chromatography to give the title compound. MS(APCI):304 (M−H).

EXAMPLE BB-16

[1011] 6-tert-Butyl-5-(toluene-4-sulfonylsulfanyl)-indole-1-carboxylicAcid Tert-Butyl Ester

[1012] The title compound was prepared according to General Method 15using 6-tert-butyl-5-mercapto-indole-1-carboxylic acid tert-butyl ester(prepared in Example FF), pyridine, tosyl bromide, carbon tetrachloride,and EtOAc.

EXAMPLE GG

[1013] 6-tert-Butyl-indole-1-carboxylic Acid Tert-Butyl Ester

[1014] (5-tert-Butyl-2-methyl-phenyl)-carbarnic acid tert-butyl ester(prepared in Example CC; 19.7 g, 75 mmol) in 100 mL of THF was cooled to−40° C. To it was added tert-butyllithium (1.5 M, 100 mL, 150 mmol),dropwise with stirring, at −45° C. to −35° C. After the addition wascomplete, the reaction was stirred at −35° C. for another 15 minutes.DMF (10.97 g, 150 mmol) was added dropwise, and the reaction mixture wasstirred at −35° C. for 30 minutes, followed by slow warming to roomtemperature. The reaction was quenched with saturated NH₄Cl solution anddiluted with EtOAc. The organic layer was washed with brine, dried(MgSO₄), and concentrated. The residue was dissolved in 100 mL of THFand 2 mL of concentrated HCl and stirred at room temperature for 1 hour.EtOAc was added, and the solution was washed with saturated NaHCO₃solution and brine and dried (MgSO₄). Concentration gave a residue thatwas purified by flash silica gel chromatography (5%-50% EtOAc inhexanes). MS(APCI): 274 (M+H).

EXAMPLE HH

[1015] 6-tert-Butyl-2,3-dihydro-indole-1-carboxylic Acid Tert-ButylEster

[1016] 6-tert-Butyl indole-1-carboxylic acid tert-butyl ester (preparedin Example GG; 13.0 g, 48 mmol) was taken up in 500 mL of AcOH. 20% Pd/C(2 g) was added, and the mixture was shaken under a hydrogen atmosphereof 50 psi. The catalyst was filtered, and the filtrate was concentrated.The residue was dissolved in EtOAc, washed with saturated NaHCO₃solution and brine, and dried (MgSO₄). Concentration gave the titlecompound which was used without purification in the next step.

EXAMPLE II

[1017] 6-tert-Butyl-2,3-dihydro-1H-indole

[1018] 6-tert-Butyl-2,3-dihydro-indole-1-carboxylic acid tert-butylester (Prepared in Example HH; 12.0 g) in CH₂Cl₂ (100 mL) was cooled to0° C. and treated with HCl gas for 10 minutes. The reaction mixture waswarmed to room temperature and stirred for 1 hour. The solvents wereevaporated; the residue was dissolved in EtOAc, washed with saturatedNaHCO₃ solution and brine, and dried (MgSO₄.) Concentration gave thetitle compound which was used without any further purification.MS(APCI): 176 (M+H).

EXAMPLE JJ

[1019] 6-tert-Butyl-5-thiocyanato-2,3-dihydro-1H-indole

[1020] The title compound was prepared according to General Method 13using 6-tert-butyl-2,3-dihydro-1H-indole (prepared in Example II; 8.3 g,47 mmol), MeOH (100 mL), sodium thiocyante (23.1 g, 284.57 mmol), NaBr(5.86 g, 56.92 mmol) and bromine (9.1 g, 56.92 mmol). The crude reactionmixture was purified by flash silica gel chromatography (5%-75% EtOAc inhexanes). MS(APCI): 233 (M+H).

EXAMPLE KK

[1021] 6-tert-Butyl-5-thiocyanato-2,3-dihydro-indole-1-carboxylic AcidTert-Butyl Ester

[1022] The title compound was prepared in the manner described inExample CC using 6-tert-butyl-5-thiocyanato-2,3-dihydro-1H-indole(prepared in Example JJ; 2.0 g, 8.6 mmol), di-t-butyl dicarbonate (2.35g, 10.8 mmol) and hexanes (150 mL). The crude product was purified byflash silica gel chromatography.

EXAMPLE LL

[1023] 6-tert-Butyl-5-mercapto-2,3-dihydro-indole-1-carboxylic AcidTert-Butyl Ester

[1024] The title compound was prepared according to General Method 14using 6-tert-butyl-5-thiocyanato-2,3-dihydro-indole-1-carboxylic acidtert-butyl ester (prepared in Example KK; 2.0 g, 6.6 mmol),dithiothreitol (1.21 g, 7.9 mmol), EtOH (100 mL), and phosphate buffer(pH: 7.5, 10 mL). The crude product was used without any purification.

EXAMPLE BB-17

[1025]6-tert-Butyl-5-(toluene-4-sulfonylsulfanyl)-2,3-dihydro-indole-1-carboxylicAcid Tert-Butyl Ester

[1026] The title compound was prepared according to General Method 15using 6-tert-Butyl-5-mercapto-2,3-dihydro-indole-1-carboxylic acidtert-butyl ester (prepared in Example FF), pyridine, tosyl bromide,carbon tetrachloride, and EtOAc.

EXAMPLE MM

[1027]4-(6-tert-Butyl-5-thiocyanato-2,3-dihydro-indole-1-sulfonyl)-benzonitrile

[1028] 6-tert-Butyl-5-thiocyanato-2,3-dihydro-1H-indole (prepared inExample JJ; 4.5 g, 19 mmol) was taken in CH₂Cl₂ (50 mL) and treated with4-cyanophenylsulfonyl chloride (3.91 g, 19.4 mmol) and pyridine (5 mL).The reaction mixture was stirred overnight, quenched with saturatedNaHCO₃ solution, and diluted with EtOAc. The organic layer wasseparated, dried (MgSO₄), and concentrated. The crude product waspurified by flash chromatography (20%-75% EtOAc in hexanes as eluents).MS(APCI): 397 (M⁺).

EXAMPLE NN

[1029]4-(6-tert-Butyl-5-mercapto-2,3-dihydro-indole-1-sulfonyl)-benzonitrile

[1030] The title compound was prepared according to the General Method14b using4-(6-tert-butyl-5-thiocyanato-2,3-dihydro-indole-1-sulfonyl)-benzonitrile(prepared in Example MM; 6.0 g, 15 mmol), sodium hydrogen sulfide (2.53g, 45.3 mmol), sodium borohydride (3.43 g, 90.7 mmol), MeOH (10 mL),water (5 mL), and AcOH (5 mL). The crude product was used furtherwithout any purification.

EXAMPLE OO-1

[1031] 2,2,2-Trifluoro-N-(5-isopropyl-2-nitro-phenyl)-acetamide

[1032] Trifluoroacetic anhydride (50 mL) was cooled to 0° C. and treateddropwise with 3-isopropyl-phenylamine (5 g, 37.03 mmol). To theresulting solution was added potassium nitrate (4.12 g, 101.1 μ1 mmol).After 1 hour, the reaction mixture was warmed to room temperature andstirred overnight. The reaction mixture was diluted carefully with icewater and extracted with EtOAc (4×100 mL). The organic layer was washedwith saturated NaHCO₃ solution and brine, dried (MgSO₄), andconcentrated. The crude product was used further without anypurification. MS(APCI): 275 (M−H).

EXAMPLE OO-2

[1033] N-(5-tert-Butyl-2-nitro-phenyl)-2,2,2-trifluoro-acetamide

[1034] The title compound was prepared following the procedure used inExample OO-1 using trifluoroacetic anhydride (300 mL),3-tert-butyl-phenylamine (144 g, 951 mmol), and potassium nitrate (106g, 1047 mmol). The crude product was used further without anypurification. MS(APCI): 289 (M−H).

EXAMPLE PP-1

[1035] 5-Isopropyl-2-nitro-phenylamine

[1036] 2,2,2-Trifluoro-N-(5-isopropyl-2-nitro-phenyl)-acetamide(prepared in Example OO-1; 9.4 g, 34 mmol) was dissolved in MeOH (30 mL)and treated with 7% aqueous potassium carbonate solution. The reactionmixture was stirred overnight at room temperature. The reaction wasdiluted with water (30 mL) and extracted with EtOAc (3×50 mL). Theorganic layer was washed with saturated NaHCO₃ solution and brine, dried(MgSO₄), and concentrated. The crude product was used further withoutany purification. MS(APCI): 181 (M+H).

EXAMPLE PP-2

[1037] 5-tert-Butyl-2-nitro-phenylamine

[1038] The title compound was prepared as outlined in Example PP-1 fromN-(5-tert-butyl-2-nitro-phenyl)-2,2,2-trifluoro-acetamide (prepared inExample OO-2; 248 g, 855 mmol), MeOH (500 mL), and 7% aqueous potassiumcarbonate solution. The crude product was used without any purification.MS(APCI): 195 (M+H).

EXAMPLE QQ-1

[1039] 5-Isopropyl-2-nitro-4-thiocyanato-phenylamine

[1040] The title compound was prepared according to General Method 13using 5-isopropyl-2-nitro-phenylamine (prepared in Example PP-1; 5.4 g,30 mmol), sodium thiocyanate (14.6 g, 180 mmol), sodium bromide (3.7 g,35.99 mmol), bromine (5.75 g, 36.0 mmol), and MeOH (100 mL). The crudereaction mixture was purified by flash silica gel chromatography (5%-50%EtOAc in hexanes as eluents). MS(APCI): 238 (M+H).

EXAMPLE QQ-2

[1041] 5-tert-Butyl-2-nitro-4-thiocyanato-phenylamine

[1042] The title compound was prepared according to the General Method13 using 5-tert-butyl-2-nitro-phenylamine (prepared in Example PP-2; 170g, 876 mmol), ammonium thiocyanate (400 g, 5260 mmol), bromine (140 g,876 mmol), and MeOH (500 mL). The crude reaction mixture was purified byflash silica gel chromatography (5%-50% EtOAc in hexanes as eluents).MS(APCI): 252 (M+H).

EXAMPLE RR-1

[1043] 4-Isopropyl-5-thiocyanato-benzene-1,2-diamine

[1044] 5-Isopropyl-2-nitro-4-thiocyanato-phenylamine (prepared inExample QQ-1; 7.83 g, 33 mmol) was hydrogenated using Raney nickel (2 g)and THF (100 mL) in the presence of hydrogen (50 psi) as described inGeneral Method 3. MS(APCI): 208(M+H).

EXAMPLE RR-2

[1045] 4-tert-Butyl-5-thiocyanato-benzene-1,2-diamine

[1046] 5-tert-Butyl-2-nitro-4-thiocyanato-phenylamine (prepared inExample QQ-2; 3 g, 12 mmol) was hydrogenated using Raney nickel (0.75 g)in the presence of hydrogen as described in General Method 3. MS(APCI):222(M+H).

EXAMPLE SS-1

[1047](2-tert-Butyoxycarbonylamino-4-isopropyl-5-thiocyanato-phenyl)-carbamicAcid Tert-Butyl Ester

[1048] Boc protection was performed as described in Example CC using4-isopropyl-5-thiocyanato-benzene-1,2-diamine (prepared in Example RR-1;4.49 g, 21.7 mmol), di-t-butyl dicarbonate (11.3 g, 52.0 mmol), hexanes(150 mL), and EtOAc (50 mL). The crude product was purified by flashsilica gel chromatography. MS(APCI): 406 (M−H).

EXAMPLE SS-2

[1049](2-tert-Butoxycarbonylamino-4-tert-Butyl-5-thiocyanato-phenyl)-carbamicAcid Tert-Butyl Ester

[1050] Boc protection was performed as described in Example CC using4-tert-butyl-5-thiocyanato-benzene-1,2-diamine (prepared in ExampleRR-2; 9.78 g, 44.2 mmol), di-t-butyl dicarbonate (23.2 g, 106 mmol),hexanes (150 mL), and EtOAc (50 mL). The crude product was purified byflash silica gel chromatography. MS(APCI): 422 (M+H).

EXAMPLE TT-1

[1051](2-tert-Butyoxycarbonylamino-4-isopropyl-5-mercapto-phenyl)-carbamicAcid Tert-Butyl Ester

[1052] The title compound was prepared according to General Method 14busing(2-tert-butyoxycarbonylamino-4-isopropyl-5-thiocyanato-phenyl)-carbamicacid tert-butyl ester (prepared in Example SS-1; 9 g, 22 mmol), sodiumhydrogen sulfide (3.7 g, 66 mmol), sodium borohydride (5.02 g, 132mmol), MeOH (20 mL), H₂O (5 mL), and AcOH (2 mL). The crude product wasused without any purification. MS(APCI): 381 (M−H).

EXAMPLE TT-2

[1053](2-tert-Butoxycarbonylamino-4-tert-Butyl-5-mercapto-phenyl)-carbamicAcid Tert-Butyl Ester

[1054] The title compound was prepared according to General Method 14busing(2-tert-butoxycarbonylamino-4-tert-butyl-5-thiocyanato-phenyl)-carbamicacid tert-butyl ester (prepared in Example SS-2; 18 g, 43 mmol), sodiumhydrogen sulfide (7.2 g, 128 mmol), sodium borohydride (9.7 g, 256mmol), MeOH (150 mL), H₂O (50 mL), and AcOH (10 mL). The crude productwas used without purification.

EXAMPLE UU-1

[1055] Toluene-4-thiosulfonic acidS-(4,5-bis-tert-butoxycarbonylamino-2-isopropyl-phenyl) Ester

[1056] The title compound was prepared according to the General Method15 using(2-tert-butyoxycarbonylamino-4-isopropyl-5-merccapto-phenyl)-carbamicacid tert-butyl ester (prepared in Example TT-1; 22.1 mmol), tosylbromide (5.2 g, 22 mmol), pyridine (5 mL), and EtOAc (50 mL). The crudeproduct was purified by flash chromatography (5%-60% EtOAc in hexanes aseluents). ¹H-NMR (CDCl₃): δ 0.97 (s, 6H), 1.53 (s, 18H), 2.4 (s, 3H),3.2 (m, 1H). 7.11 (br s, 1H), 7.22 (d, 2H), 7.28 (s, 1H), 7.36 (s, 1H),7.5 (d, 2H), 7.75 (br s, 1H).

EXAMPLE UU-2

[1057] Toluene-4-thiosulfonic acidS-(4,5-bis-tert-butoxycarbonylamino-2-tert-butyl-phenyl) Ester

[1058] The title compound was prepared according to the General Method15 using(2-tert-butoxycarbonylamino-4-tert-butyl-5-mercapto-phenyl)-carbamicacid tert-butyl ester (prepared in Example TT-2; 16.9 g, 42.8 mmol),tosyl bromide (10.04 g, 42.76 mmol), pyridine (10 mL), and EtOAc (150mL). The crude product was purified by flash chromatography (5%-60%EtOAc in hexanes as eluents). ¹H-NMR (CDCl₃): δ 1.19 (s, 9H), 1.53 (s,18H), 2.42 (s, 3H), 6.42 (br s, 1H), 7.22 (d, 2H), 7.28 (s, 1H), 7.5 (m,3H), 7.87 (br s, 1H).

EXAMPLE VV-1

[1059] Toluene-4-thiosulfonic acid S-(4,5-diamino-2-isopropyl-phenyl)Ester

[1060] Toluene-4-thiosulfonic acidS-(4,5-bis-tert-butoxycarbonylamino-2-isopropyl-phenyl) ester (preparedin Example UU-1; 8.88 g, 16.6 mmol) was dissolved in CH₂Cl₂ (25 mL), andHCl gas was bubbled through the solution for 15 minutes. The reactionmixture was stirred at room temperature for 90 minutes. The solventswere evaporated, and the residue was dissolved in MeOH (10 mL) andtreated with pH 7.5 buffer. The precipitate that formed was filtered anddried. MS(APCI): 337 (M+H).

EXAMPLE VV-2

[1061] Toluene-4-thiosulfonic acid S-(4,5-diamino-2-tert-butyl-phenyl)Ester

[1062] The title compound was prepared as described in Example VV-1 fromtoluene-4-thiosulfonic acidS-(4,5-bis-tert-butoxycarbonylamino-2-tert-butyl-phenyl) ester (preparedin Example UU-2; 15 g, 28 mmol), CH₂Cl₂ (100 mL), and HCl gas. MS(APCI):351 (M+H).

EXAMPLE BB-19

[1063] Toluene-4-thiosulfonic acid S-(6-isopropyl-3H-benzoimidazol-5-yl)Toluene-4-thiosulfonic acid S-(1,2-diamino-5-isopropyl-phenyl)ester(prepared in Example VV-1; 0.5 g) was dissolved in 96% formic acid (0.5mL) and refluxed for 3 hours. After cooling, toluene (10 mL) and water(5 mL) were added. The organic layer was concentrated; the residue wastaken in EtOAc (20 mL), washed with H₂O, and dried (MgSO₄).Concentration gave the crude title compound which was purified by flashchromatography (20%-100% EtOAc in hexanes to 2%-8% MeOH in CH₂Cl₂ aseluents). MS(APCI): 347 (M+H).

EXAMPLE BB-20

[1064] Toluene-4-thiosulfonic acid S-(6-tert-butyl-3H-benzoimidzol-5-yl)Ester

[1065] The title compound was prepared using the procedure outlined inExample BB-19 from toluene-4-thiosulfonic acidS-(1,2-diamino-5-tert-butyl-phenyl)ester (prepared in Example VV-2; 0.5g), and 96% formic acid (0.5 mL) The crude product was purified by flashchromatography (20%-100% EtOAc in hexanes to 2%-8% MeOH in CH₂Cl₂ aseluents). MS(APCI): 361 (M+H).

EXAMPLE BB-21

[1066] Toluene-4-thiosulfonic acidS-(6-tert-butyl-2-oxo-2,3-dihydro-1H-benzoimidzol-5-yl) Ester

[1067] Toluene-4-thiosulfonic acidS-(4,5-diamino-2-tert-butyl-phenyl)ester (prepared in Example VV-2; 0.4g, 1.2 mmol) and triphosgene (0.12 g, 0.41 mmol) were taken in THF (30mL). To it triethylamine (1 mL) was added. The reaction mixture was keptat 90° C. for 1.5 hours. The crude reaction mixture was subjected toflash silica gel chromatography (EtOAc to 2%-10% MeOH in CH₂Cl₂ aseluents). MS(APCI): 375 (M−H).

[1068] Preparation of 2-substitued-Indoles for the Synthesis of BB-22

EXAMPLE WW

[1069] 4-tert-Butyl-1-methyl-2-nitrobenzene

[1070] Nitration was performed as described in General Method 12 usingtert-butyl-4-methylbenzene (25 g), concentrated H₂SO₄ (92 g), 70% HNO3(82 g), and H₂O (25 g). The crude product was purified via distillationunder vacuum.

EXAMPLE XX

[1071] 3-(4-tert-Butyl-2-nitro-phenyl)-2-oxo-propionic Acid Ethyl Ester

[1072] The title compound was prepared by adapting the proceduredescribed by Gagliardi S., et al., in J. Med. Chem., 1998;41:1568 usingpotassium (1.66 g, 42.4 mmol), Et₂O (200 mL), EtOH (10 mL), diethyloxalate (7.56 g, 51.8 mmol), and 4-tert-butyl-1-methyl-2-nitrobenzene(prepared in Example WW; 10.0 g, 51.8 mmol). MS(APCI): 294 (M+H).

EXAMPLE YY

[1073] 6-tert-Butyl-1H-indole-2-carboxylic Acid Ethyl Ester

[1074] A mixture of 3-(4-tert-butyl-2-nitro-phenyl)-2-oxo-propionic acidethyl ester (prepared in Example XX; 9.1 g, 31 mmol), iron powder (15.3g, 274 mmol). EtOH (70 mL), and glacial AcOH (70 mL) was refluxed for 2hours. After cooling, the resulting mixture was evaporated. THF (100 mL)was added to the residue, and the suspension was filtered on florisil,eluting with a large amount of THF. The solvents were evaporated, andthe residue was purified by flash silica gel chromatography (5%-30%EtOAc in hexanes as eluents). MS(APCI): 246 (M+H).

EXAMPLE ZZ

[1075] 6-tert-Butyl-5-thiocyanato-1H-indole-2-carboxylate Ethyl Ester

[1076] The title compound was prepared according to General Method 13using 6-tert-butyl-1H-indole-2-carboxylic acid ethyl ester (prepared inExample YY; 3.5 g, 14 mmol), ammonium thiocyanate (1.63 g, 21.4 mmol),bromine (3.42 g, 21.4 mmol), and MeOH (50 mL). The crude product waspurified by flash silica gel chromatography (5%-50% EtOAc in hexanes aseluents). MS(APCI): 301 (M−H).

EXAMPLE AAA

[1077] (6-tert-Butyl-5-mercapto-1H-indole-2-carboxylic Acid Ethyl Ester

[1078] The title compound was prepared according to the general Method14b using (6-tert-butyl-5-thiocyanato-1H-indole-2-carboxylic acid ethylester (prepared in Example ZZ; 0.25 g, 0.83 mmol), sodium hydrogensulfide (0.13 g, 2.48 mmol), sodium borohydride (0.188 g, 4.98 mmol),MeOH (5 mL), and AcOH (1 mL). MS(APCI): 278 (M+H).

EXAMPLE BB-22

[1079]6-tert-Butyl-5-(toluene-4-sulfonylsulfanyl)-1H-indole-2-carboxylic AcidEthyl Ester

[1080] The title compound was prepared according to General Method 15using (6-tert-Butyl-5-mercapto-1H-indole-2-carboxylic acid ethyl ester(prepared in Example AAA), pyridine, tosyl bromide, carbontetrachloride, and EtOAc.

[1081] Preparation of Quinoxalones for the Synthesis of BB-23

EXAMPLE BBB

[1082] (5-tert-Butyl-2-nitro-4-thiocyanatophenyl)-oxalmic Acid MethylEster

[1083] 5-tert-Butyl-2-nitro-4-thiocyanato-phenylamine (prepared inExample QQ-2; 2.5 g, 10.0 mmol) and methyl chloroxoacetate (5 mL) weredissolved in CH₂Cl₂ (50 mL) and treated with pyridine (5 mL.) Thereaction mixture was stirred at room temperature overnight, quenchedwith saturated NaHCO₃ solution, and diluted with EtOAc (100 mL). Theorganic layer was washed with dil HCl and brine, dried (MgSO₄), andconcentrated. The crude product was used without purification. MS(APCI):336 (M−H).

EXAMPLE CCC

[1084] 6-tert-Butyl-7-thiocyanato-1,4-dihydro-quinoxaline-2,3-dione

[1085] (5-tert-Butyl-2-nitro-4-thiocyanatophenyl)-oxalmic acid methylester (prepared in Example BBB; 3.91 g, 11.6 mmol) was taken up in THF(100 mL) and treated with Raney nickel (1 g). The reaction mixture wasshaken in a hydrogen atmosphere (50 psi). The catalyst was filtered; thefiltrate was concentrated, and the residue was triturated withEtOAc/hexanes to obtain the title compound. MS(APCI): 274 (M−H).

EXAMPLE DDD

[1086] 6-tert-Butyl-7-mercapto-1,4-dihydro-quinoxaline-2,3-dione

[1087] The title compound was prepared according to General Method 14busing 6-tert-butyl-7-thiocyanato-1,4-dihydro-quinoxaline-2,3-dione(prepared in Example CCC; 1.5 g, 9.1 mmol), sodium hydrogen sulfide(0.51 g, 27 mmol), sodium borohydride (2.1 g, 55 mmol). MeOH (30 mL),H₂O (3 mL), and glacial AcOH (5 mL). The crude product was used withoutpurification. MS(APCI): 251 (M+H).

EXAMPLE BB-23

[1088] Toluene-4-thiosulfonic acidS-(7-tert-butyl-2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-6-yl) Ester

[1089] The title compound was prepared according to the General Method15 using 6-tert-butyl-7-mercapto-1,4-dihydro-quinoxaline-2,3-dione(prepared in Example DDD, 9.1 mmol), tosyl bromide (2.1 g, 9.1 mmol),pyridine (2 mL), EtOAc (50 mL). The crude product was purified by flashsilica gel chromatography (5%-10% MeOH in CH₂Cl₂) as eluents. MS(APCI):405 (M+H).

[1090] General Method 16a. Coupling of the Dihydropyrone and theThiotosylate

[1091] The appropriate dihydropyrone intermediate (1 equiv.) from TableF or Table J was added to a reaction flask followed by DMF (1-12 mL permmol of dihydropyrone). Potassium carbonate (K₂CO₃) (4-8 equiv.) wasadded followed by the appropriate thiotosylate reagent (1.1-1.5 eq.)from Table K. The reaction was stirred at room temperature (2.5 hours toovernight). The reaction was worked up by pouring into a mixture ofEtOAc and either 1N HCl or saturated aqueous NH₄Cl. The layers wereseparated and the aqueous layer extracted again with EtOAc. The combinedorganic extracts were washed with brine, dried (MgSO₄), andconcentrated. The final compounds were purified via recrystallization,trituration, or silica gel gel chromatography.

[1092] General Method 16b. Coupling of the Dihydropyrone and theThiotosylate

[1093] The appropriate dihydropyrone intermediate (1 equiv.) fromExamples E-1 to E-46 or Examples J-1 to J-12 and the appropriatethiotosylate reagent (1.0-1.5 equiv.) from Examples BB-1 to BB-14 wereadded to a reaction flask, followed by acetonitrile (1-12 mL per mmol ofdihydropyrone) and triethylamine (NEt₃; 2-4 equiv.) The reaction wasstirred at room temperature (2.5 hours to overnight.) The NEt₃ andsolvent were evaporated, and the reaction was poured into a mixture ofEtOAc and either saturated aqueous NH₄Cl or water. The aqueous layer wasextracted with EtOAc; the combined organic extracts were dried (MgSO₄),and concentrated. The final compounds were purified viarecrystallization, trituration, or silica gel gel chromatography.

EXAMPLE 1

[1094]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-pyridin-4-yl-ethyl)-5,6-dihydro-pyran-2-one

[1095] The title compound was prepared as described in General Method16a using4-hydroxy-6-isopropyl-6-(2-pyridin-4-yl-ethyl)-5,6-dihydro-pyran-2-one(Example E-15; 0.8 mmol), toluene-4-thiosulfonic acidS-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 0.9mmol), potassium carbonate (3.1 mmol) in DMF (5 mL). The product wastriturated from Et₂O, mp 140-155° C. MS (APCI): 470 (M+H).

EXAMPLE 2

[1096]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-pyridin-3-yl-ethyl)-5,6-dihydro-pyran-2-one

[1097] The title compound was prepared as described in General Method16a using4-hydroxy-6-isopropyl-6-(2-pyridin-3-yl-ethyl)-5,6-dihydro-pyran-2-one(Example E-16; 0.92 mmol), toluene-4-thiosulfonic acidS-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2;1.01 mmol), potassium carbonate (3.67 mmol) in DMF (5 mL). The productwas triturated from Et₂O, mp 122-125° C. MS (APCI): 470 (M+H).

EXAMPLE 3

[1098]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-pyridin-2-yl-ethyl)-5,6-dihydro-pyran-2-one

[1099] The title compound was prepared as described in General Method16a using4-hydroxy-6-isopropyl-6-(2-pyridin-2-yl-ethyl)-5,6-dihydro-pyran-2-one(Example E-14; 0.8 mmol), toluene-4-thiosulfonic acidS-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 0.9mmol), potassium carbonate (3.1 mmol) in DMF (5 mL). The product wastriturated from Et₂O, mp 100-110° C. MS (APCI): 470 (M+H).

EXAMPLE 4

[1100]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-6-(2-furan-3-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one

[1101] The title compound was prepared as described in General Method16a using6-(2-furan-3-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one(Example E-18; 1 mmol), toluene-4-thiosulfonic acidS-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 1.1mmol), potassium carbonate (4 mmol) in DMF (4 mL). The product was flashchromatographed over silica gel using 70:20:10 hexane:EtOAc:CH₂Cl₂, mp62-70° C. MS (APCI): 457 (M−H).

EXAMPLE 5

[1102]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-6-(2-furan-2-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one

[1103] The title compound was prepared as described in General Method16a using6-(2-furan-2-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one(Example E-17; 1 mmol), toluene-4-thiosulfonic acidS-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 1.1mmol), potassium carbonate (4 mmol) in DMF (5 mL) mp 64-110° C. MS(APCI): 457 (M−H).

EXAMPLE 6

[1104]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(tetrahydro-furan-2-yl)-ethyl]-5,6-dihydro-pyran-2-one

[1105] The title compound was prepared as described in General Method16a using4-hydroxy-6-isopropyl-6-[2-(tetrahydro-furan-2-yl)-ethyl]-5,6-dihydro-pyran-2-one(Example E-19; 0.98 mmol), toluene-4-thiosulfonic acidS-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-; 1.18mmol), potassium carbonate (3.93 mmol) in DMF (5 mL). Flashchromatographed over silica gel using 10:90 EtOAc:CH₂Cl₂, mp 57-59° C.MS (APCI): 461 (M−H).

EXAMPLE 7

[1106]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one

[1107] The title compound was prepared as described in General Method16a using4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one(Example E-20; 0.84 mmol), toluene-4-thiosulfonic acidS-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2;0.92 mmol), potassium carbonate (3.35 mmol) in DMF (4 mL). The productwas purified via flash chromatography over silica gel eluting with 10:90EtOAc:CH₂Cl₂, mp 63-70° C. MS (APCI): 475 (M+H).

EXAMPLE 8

[1108]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-2-yl-ethyl)-5,6-dihydro-pyran-2-one

[1109] The title compound was prepared as described in General Method16a using4-hydroxy-6-isopropyl-6-(2-thiophen-2-yl-ethyl)-5,6-dihydro-pyran-2-one(Example E-21; 1 mmol), toluene-4-thiosulfonic acidS-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 1.2mmol), potassium carbonate (4 mmol) in DMF (3 mL). The product wasisolated via flash chromatography over silica gel using 10:90EtOAc:CH₂Cl₂, mp 73-77° C. MS (APCI): 475 (M+H).

EXAMPLE 9

[1110]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(5-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one

[1111] The title compound was prepared as described in General Method16a using4-hydroxy-6-[2-(5-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one(Example E-23; 0.67 mmol), toluene-4-thiosulfonic acidS-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2;0.74 mmol), potassium carbonate (2.7 mmol) in DMF (5 mL), mp 76-80° C.MS (APCI): 503 (M−H).

EXAMPLE 10

[1112]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]6-isopropyl-5,6-dihydro-pyran-2-one

[1113] The title compound was prepared as described in General Method16b using4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one(Example E-24; 1 mmol), toluene-4-thiosulfonic acidS-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2;1.05 mmol), NEt₃ (2.2 mmol) in acetonitrile (5 mL). The product waschromatographed over silica gel using 97.5:2.5 CH₂Cl₂:MeOH, mp 87-90° C.MS (APCI): 503 (M−H).

EXAMPLE 11

[1114]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one

[1115] The title compound was prepared as described in General Method16b using4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one(Example E-24; 1 mmol), toluene-4-thiosulfonic acidS-(4-amino-2-tert-butyl-5-methyl-phenyl)ester (Example BB-11; 1.05mmol), NEt₃ (2.2 mmol) in acetonitrile (5 mL). The product wastriturated from Et₂O, mp 107-115° C. MS (APCI): 488 (M−H).

EXAMPLE 12 (S)

[1116](S)-3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one

[1117] The title compound was prepared as described in General Method16a using(S)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one(Example J-1 (S); 2.68 mmol), toluene-4-thiosulfonic acidS-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2;3.22 mmol), potassium carbonate (10.74 mmol) in DMF (5 mL), mp 64-70° C.MS (APCI): 475 (M+H).

EXAMPLE 13

[1118](S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-isopropyl-6-phenethyl-5,6-dihydro-pyran-2-one

[1119] The title compound was prepared according to the General Method16a using tolune-4-thiosulfonic acidS-(2-amino-5-tert-butyl-benzothiazol-6-yl)ester (Example BB-1; 0.6 g,1.53 mmol),(S)-4-hydroxy-6-isopropyl-6-phenylethyl-5,6-dihydro-pyran-2-one (ExampleJ-11 (S); 0.4 g, 1.53 mmol), potassium carbonate (0.8 g), and DMF (DMF;5 mL). The crude reaction mixture was purified by flash chromatography(25% EtOAc in hexanes to 50% EtOAc in hexanes to 10% MeOH in EtOAc aseluents), mp 186-188° C. MS (APCI): 497 (M+H).

EXAMPLE 14

[1120](S)-3-(2-Amino-5-isopropyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-isopropyl-6-phenethyl-5,6-dihydro-pyran-2-one

[1121] The title compound was prepared according to the General Method16b using (S)-4-hydroxy-6-isopropyl-6-phenethyl-5,6-dihydro-pyran-2-one(Example J-11 (S); 0.5 g, 1.92 mmol), toluene-4-thiosulfonic acidS-(2-amino-5-isopropyl-benzothiazol-6-yl)ester (Example BB-3; 0.73 g,1.92 mmol), NEt₃ (0.39 g, 3.84 mmol), and acetonitrile (10 mL). Thecrude compound was purified by flash silica gel chromatography (25%EtOAc in hexanes to 100% EtOAc to 5% MeOH in EtOAc as eluents), mp197-199° C. MS (APCI): 483 (M+H).

EXAMPLE 15

[1122]6-[-2-(4-Fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-3-(5-isopropyl-benzothiazol-6-ylsulfanyl)-5,6-dihydro-pyran-2-one

[1123] The title compound was prepared according to General Method 16busing6-[(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydropyran-2-one(Example E-27; 0.5 g, 1.8 mmol), toluene-4-thiosulfonic acidS-(5-isopropyl-benzothiazol-6-yl)ester (Example BB-4; 0.65 g, 1.8 mmol),NEt₃ (0.22 g, 2.16 mmol), and acetonitrile (10 mL). The crude compoundwas purified by flash silica gel chromatography (25% EtOAc in hexanes to100% EtOAc to 5% MeOH in EtOAc as eluents), mp 104-105° C. MS (APCI):486.

EXAMPLE 16

[1124]3-(2-Amino-5-isopropyl-benzothiazol-6-yl-sulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-phenethyl-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one

[1125] The title compound was prepared according to General Method]6busing6-[(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one(Example E-27; 0.5 g, 1.8 mmol), toluene-4-thiosulfonic acidS-(2-amino-5-isopropyl-benzothiazol-6-yl)ester (Example BB-3; 0.68 g,1.8 mmol), NEt₃ (0.36 g, 3.6 mmol), and acetonitrile (20 mL). The crudecompound was purified by flash silica gel chromatography (25% EtOAc inhexanes to 100% EtOAc to 5% MeOH in EtOAc as eluents), mp 204-206° C. MS(APCI): 501 (M+H).

EXAMPLE 17

[1126](S)-3-(2-Amino-7-isopropyl-4-methyl-benzothiazol-6-yl-sulfanyl)-4-hydroxy-6-isopropyl-6-phenethyl-5,6-dihydro-pyran-2-one

[1127] The title compound was prepared according to General Method 16ausing toluene-4-thiosulfonic acidS-(2-amino-7-isopropyl-4-methyl-benzothiazol-6-yl)ester (Example BB-5;0.75 g, 1.92 mmol),(S)-4-hydroxy-6-isopropyl-6-phenylethyl-5,6-dihydro-pyran-2-one (ExampleJ-1 I (S); 0.5 g, 1.92 mmol), potassium carbonate (1.0 g), and DMF (5mL). The crude reaction mixture was purified by flash chromatography(25% EtOAc in hexanes to 50% EtOAc in hexanes to 5% MeOH in EtOAc aseluents), mp 160-162° C. MS (APCI): 497 (M+H).

EXAMPLE 18

[1128](S)-3-(2-Amino-7-isopropyl-4-methyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-[2-(4-hydroxyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one

[1129] The title compound was prepared according to General Method 16ausing toluene-4-thiosulfonic acidS-(2-amino-7-isopropyl-4-methyl-benzothiazol-6-yl)ester (Example BB-5;0.35 g, 1.27 mmol),(S)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one(Example J-10; 0.35 g. 1.27 mmol), potassium carbonate (0.7 g), and DMF(5 mL). The crude reaction mixture was purified by flash chromatography(20% EtOAc in hexanes to 50% EtOAc in hexanes to 5% MeOH in EtOAc aseluents), mp 232-234° C. MS (APCI): 513 (M+H).

EXAMPLE 19

[1130](S)-(6-{4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-4-isopropyl-7-methyl-benzothiazol-2-yl)-carbamicAcid Methyl Ester

[1131] The title compound was prepared according to General Method 16ausing toluene-4-thiosulfonic acidS-[2-(methyloxycarbonyl)amino]-4-isopropyl-7-methyl-benzothiazol-6-yl)ester(Example BB-6; 0.65 g, 1.5 mmol),(S)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one(Example J-10 (S); 0.4 g, 1.5 mmol), potassium carbonate (0.7 g), andDMF (5 mL). The crude reaction mixture was purified by flashchromatography (30% EtOAc in hexanes to 100% EtOAc as eluents), mp150-151° C. MS (APCI): 571 (M+H).

EXAMPLE 20

[1132](S)-3-(2-Amino-6-tert-butyl-benzothiazol-4-ylsulfanyl)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one

[1133] The title compound was prepared according to General Method 16ausing toluene-4-thiosulfonic acidS-(2-amino-6-tert-butyl-benzothiazol-4-yl)ester (Example BB-7; 0.28 g,0.73 mmol),(S)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one(Example J-10 (S); 0.2 g, 0.73 mmol), potassium carbonate (0.7 g), andDMF (5 mL). The crude reaction mixture was purified by flashchromatography (30% EtOAc in hexanes to 100% EtOAc to 10% MeOH in CH₂Cl₂in as eluents), mp 168-179° C. MS (APCI): 513 (M+H).

EXAMPLE 21

[1134](S)-3-(3-tert-Butyl-benzo[b]thiophen-2-ylsulfanyl)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one

[1135] The title compound was prepared according to General Method 16ausing(S)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one(Example J-10 (S); 0.052 g, 0.19 mmol), toluene-4-thiosulfonic acidS-(3-tert-butyl-benzo[b]thiophen-2-yl) ester (Example BB-8; 0.080 g,0.21 mmol), potassium carbonate (0.029 g, 0.21 mmol), and DMF (1.0 mL).The product was purified via column chromatography (eluting with 1:1hexanes:EtOAc) to provide a solid, mp 207° C.

[1136]¹H NMR (DMSO-d₆): δ 0.86-0.92 (m, 6H), 1.56 (s, 9H), 1.85-1.95 (m,2H), 2.09-2.21 (m, 3H), 2.52 (d, 1H), 2.92 (d, 1H), 6.62 (d, 2H), 6.93(d, 2H), 7.12 (t, 1H), 7.21 (t, 1H), 7.40 (d, 1H), 7.89 (d, 1H), 9.14(s, 1H).

EXAMPLE 22

[1137]3-(3-tert-Butyl-benzo[b]thiophen-2-yl-sulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one

[1138] The title compound was prepared according to General Method 16ausing4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one(Example E-34; 0.20 g, 0.73 mmol), toluene-4-thiosulfonic acidS-(3-tert-butyl-benzo[b]thiophen-2-yl)ester (Example BB-8; 0.302 g,0.803 mmol), potassium carbonate (0.11 g, 0.80 mmol), and DMF (2.0 mL).The product was purified via column chromatography (eluting with EtOAc)to the title compound, mp 92-94° C.

[1139]¹H NMR (DMSO-d₆): δ 0.93-0.99 (m, 6H), 1.61 (s, 9H), 2.13-2.28 (m,3H), 2.47-2.71 (m, 3H), 2.99 (d, 1H), 4.50 (dd, 2H), 7.09-7.28 (m, 5H),7.35 (d, 1H), 7.42 (d, 1H), 7.93 (d, 1H).

EXAMPLE 23

[1140]4-Hydroxy-3-(5-hydroxymethyl-2-isopropyl-thiophen-3-ylsulfanyl)-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one

[1141] The title compound was prepared according to General Method 16busing4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one(Example E-20; 0.200 g, 0.75 mmol), toluene-4-thiosulfonic acidS-[5-(tert-butyl-dimethyl-silanyloxymethyl)-2-isopropyl-thiophen-3-yl]ester(Example BB-9; 0.377 g, 0.83 mmol), NEt₃ (0.209 mL, 1.50 mmol), andacetonitrile (1.5 mL). As part of the purification, the silylether wascleaved by dissolving the crude coupled product in THF (50 mL) and thentreated with a 1.0 M THF solution of tetrabutylammoniumflouride (1.5 mL,1.5 mmol). After 30 minutes, the mixture was diluted with H₂O andextracted with EtOAc. The organic layers were then combined, dried(MgSO₄), and concentrated. The resulting residue was then submitted tocolumn chromatography (eluting with 3% MeOH in CH₂Cl₂) to provide thetitle compound, mp 52-54° C.

[1142]¹H NMR (CDCl₃): δ 0.96-1.03 (m, 6H), 1.32 (t, 6H), 1.92-2.09 (m,2H), 2.17-2.26 (m, 1H), 2.49 (d, 1H), 2.66 (t, 2H), 2.93 (d, 1H), 3.71(sept., 1H), 4.57 (s, 2H), 6.71 (s, 1H), 6.79 (d, 1H), 6.84 (bs, 1H),7.23-7.24 (m, 1H), 7.83 (s, 1H).

EXAMPLE 24

[1143]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiazol-5-yl)-ethyl]-5,6-dihydro-pyran-2-one

[1144] The title compound was prepared according to General Method 16ausing4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiazol-5-yl)-ethyl]-5,6-dihydro-pyran-2-one(Example E-1; 0.22 g, 0.78 mmol), toluene-4-thiosulfonic acidS-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl) ester (Example BB-2;0.33 g, 0.90 mmol), potassium carbonate (1.0 g, 7.2 mmol), and DMF (4mL). The product was chromatographed on silica gel, eluting with 10%MeOH in CH₂Cl₂, to give the title compound, mp 138-141° C.

[1145]¹H NMR (DMSO-d₆): δ 0.90-0.96 (m, 6H), 1.46 (s, 9H), 1.85 (s, 3H),1.95-2.00 (m, 2H), 2.15-2.23 (m, 4H), 2.70-2.82 (m, 3H), 2.93 (d of ABXq, 1H), 4.34 (s, 2H), 4.92 (br s, 1H), 6.66 (s, 1H), 7.24 (s, 1H), 8.79(s, 1H).

EXAMPLE 25

[1146]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiazol-2-yl-ethyl)-5,6-dihydro-pyran-2-one

[1147] The title compound was prepared according to General Method 16ausing4-hydroxy-6-isopropyl-6-(2-thiazol-2-yl-ethyl)-5,6-dihydro-pyran-2-one(Example E-2; 0.25 g, 0.95 mmol), toluene-4-thiosulfonic acidS-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2;0.42 g, 1.15 mmol), potassium carbonate (0.52 g, 3.76 mmol), and DMF (5mL). The product was chromatographed on silica gel, eluting with 5% MeOHin CH₂Cl₂, to give the title compound, mp 108-110° C.

[1148]¹H NMR (DMSO-d₆): δ 0.91-0.95 (m, 6H), 1.46 (s, 9H), 1.92 (s, 3H),2.18-2.24 (m, 3H), 2.77 (d of ABX q, 1H), 2.96 (d of ABX q, 1H), 3.06(br t, 2H), 4.34 (s, 2H), 4.90 (br s, 1H), 6.68 (s, 1H), 7.24 (s, 1H),7.57 (d, 1H), 7.67 (d, 1H).

EXAMPLE 26

[1149]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiazol-2-yl)-ethyl]-5,6-dihydro-pyran-2-one

[1150] The title compound was prepared according to General Method 16ausing4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiazol-2-yl)-ethyl]-5,6-dihydro-pyran-2-one(Example E-6; 0.33 g, 1.2 mmol), toluene-4-thiosulfonic acidS-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl) ester (Example BB-2;0.51 g, 1.4 mmol), potassium carbonate (0.48 g, 3.5 mmol), and DMF (5mL). The product was chromatographed on silica gel, eluting with 5% MeOHin CH₂Cl₂, to give the title compound, mp 98-100° C.

[1151]¹H NMR (DMSO-d₆): δ 0.86-0.92 (m, 6H), 1.42 (s, 9H), 1.87 (s, 3H),2.15-2.20 (m, 3H), 2.25 (s, 3H), 2.71 (d of ABX q, 1H), 2.83-2.95 (m,3H), 4.30 (s, 2H), 4.89 (br s, 1H), 6.64 (s, 1H), 7.04 (s, 1H), 7.20 (d,1H).

EXAMPLE 27

[1152]N-(4-{2-[5-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-2-isopropyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-thiazol-2-yl)-acetamide

[1153] The title compound was prepared according to General Method 16ausingN-{4-[2-(4-hydroxy-2-isopropyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-ethyl]-thiazol-2-yl}-acetamide(Example E-13; 0.49 g, 1.5 mmol), toluene-4-thiosulfonic acidS-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2;0.66 g, 1.8 mmol), potassium carbonate (0.83 g, 6.0 mmol), and DMF (5mL). The product was chromatographed on silica gel, eluting with 5% MeOHin CH₂Cl₂, to give the title compound, mp 128-130° C.

[1154]¹H NMR (DMSO-d₆): δ 0.86-0.92 (m, 6H), 1.42 (s, 9H), 1.85 (s, 3H),2.05 (m, 5H), 2.17 (m, 1H), 2.59-2.67 (m, 3H), 2.92 (d of ABX q, 1H),)4.30 (s, 2H), 4.89 (br s, 1H), 6.25 (s, 1H), 6.75 (s, 1H), 7.20 (d, 1H),11.92 (br s, 1H), 12.00 (s, 1H). TABLE L Final Dihydropyrones

Chirality Melting Exam- at Point Mass Spe ple Ar₂ C-6 Ar₁ General Method(° C.) (APCI) 28

±

16a 103-105 490(M+H) 29

±

16a 120-124 476(M+H) 30

±

16a 118-121 490(M+H) 31

±

16a 105-108 490(M+H) 32

±

16b 97-110 518(M+H) 33

±

16b 109-112 518(M+H) 34

±

16b 108-112 518(M+H) 35

±

16a 93-98 460(M+H) 36

±

16a 96-101 453(M+H) 37

±

16a 90-96 38

±

16a 104-106 490(M+H) 39

±

16a 110-117 40

±

16a 136-138 459(M+H) 41

±

16a 134-135 444(M+H) 42

±

16a 221-223 471(M+H) 43

±

16a 120-122 456(M+H) 44

±

16a 145-148 486(M+H) 45

±

16a 137-140 471(M+H) 46

±

16a 115-118 476(M+H) 47 Ph S

16b 197-199 468(M+H) 48

S

16b 142 483(M) 49

±

16a 158-160 50

S

16a 232-234 513(M+H) 51

S

16b 204-206 52

R

16a 73-85 475(M+H) 53

±

16b 107-109 551(M+H) 54

±

16a 118-123 55

±

16a 80-87 56

±

16a 70-73 57

±

16a 461(M+H) 58

±

16a 89-91 489(M+H) 59

±

16a 669 60

|

16a 663 61

±

16a 95-96 508(M+H) 62

±

16b 107-113 488(M−H) 63

S

16a 115 487(M−H) 64

±

16a 86-90 487(M−H) 65

±

16a 98-101 472(M−H) 66

±

16a 489(M+H) 67

±

16a 104-106 488(M−H) 68

±

16a 104-105 498(M+H) 69

±

16a followed by NaOH deprotection 125-126 494(M+H) 70

S

16a 138-140 647(M+H) 71

S

16a 171-173 580(M+H) 72

S

16a followed by NaOH deprotection 103-105 480(M+H) 73

S

16a followed by NaOH deprotection 123-125 464(M+H) 74

S

16a 122-124 515(M+H) 75

S

16a 222-224 451(M+H) 76

S

16a 158-160 467(M+H) 77

S

16a 203-205 465(M+H) 78

S

16a 232-234 481(M+H) 79

S

16a 152-153 573(M−H) 80

S

16a 192-194 536(M+H) 81

S

Saponification of Example 80 with LiOH 123-125 506(M−H) 82

±

16a 190-192 503(M+H) 83

±

16a 193-195 515(M+H) 84

±

16a 180-182 529(M+H) 85

S

16a 173-175 533(M+H) 86

S

16a 175-177 539(M+H) 87

S

16a 221-222 668(M+H) 88

S

16a >173 529(M+H) 89

±

16a followed by NH₃/NeOH deprotection 208-210 491 (M+1) 90

+

16a followed by HCl (g) deprotection 482(M+1) 91

+

16a followed by HCl (g) deprotection 472(M+1) 92

±

16a 155-157 659(M−1)

[1155] The Table L above shows the compounds of the invention asracemic; however, the R and S forms are within the scope of theinvention. The S form is the preferred.

[1156] The compound names corresponding to Examples 28-60 in Table Labove are:

EXAMPLE 283-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(5-methyl-thiazol-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;EXAMPLE 293-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiazol-5-yl-ethyl)-5,6-dihydro-pyran-2-one:EXAMPLE 303-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(2-methyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;EXAMPLE 313-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(5-methyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;EXAMPLE 323-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(2-isopropyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;EXAMPLE 333-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-isopropyl-thiazol-5-yl)-ethyl]-5,6-dihydro-pyran-2-one;EXAMPLE 343-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(5-isopropyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;EXAMPLE 353-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;EXAMPLE 363-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-6-(2-furan-3-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;EXAMPLE 373-(2-tert-Butyl-4-hydroxy-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(5-hydroxymethyl-thiophen-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;EXAMPLE 383-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(5-hydroxymethyl-thiophen-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;EXAMPLE 393-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(5-hydroxymethyl-thiophen-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;EXAMPLE 403-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(1H-pyrazol-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;EXAMPLE 413-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-[2-(1H-pyrazol-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;EXAMPLE 423-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-pyrimidin-5-yl-ethyl)-5,6-dihydro-pyran-2-one;EXAMPLE 433-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-pyrimidin-5-yl-ethyl)-5,6-dihydro-pyran-2-one;EXAMPLE 446-[2-(2-Amino-pyrimidin-5-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;EXAMPLE 453-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-6-[2-(2-amino-pyrimidin-5-yl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;EXAMPLE 463-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiazol-4-yl-ethyl)-5,6-dihydro-pyran-2-one;EXAMPLE 47(S)-4-Hydroxy-6-isopropyl-3-(5-isopropyl-benzothiazol-6-ylsulfanyl)-6-phenethyl-5,6-dihydro-pyran-2-one;EXAMPLE 48(S)-4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-3-(5-isopropyl-benzothiazol-6-ylsulfanyl)-5,6-dihydro-pyran-2-one;EXAMPLE 493-(2-Amino-7-isopropyl-4-methyl-benzothiazol-6-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;EXAMPLE 50(S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;EXAMPLE 51(S)-3-(2-Amino-5-isopropyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;EXAMPLE 52(R)-3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;EXAMPLE 533-(2-Amino-5-isopropyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(2-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-pyran-2-one;EXAMPLE 543-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-pyridin-3-yl-ethyl)-5,6-dihydro-pyran-2-one;EXAMPLE 553-(2-tert-Butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(5-hydroxymethyl-thiophen-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;EXAMPLE 563-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(tetrahydro-furan-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;EXAMPLE 573-(2-tert-Butyl-4-hydroxymethyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;EXAMPLE 583-[2-tert-Butyl-4-(2-hydroxy-ethyl)-5-methyl-phenylsulfanyl]-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;EXAMPLE 59 5-Trifluoromethyl-pyridine-2-sulfonic acid{5-tert-butyl-4-[4-hydroxy-6-isopropyl-2-oxo-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-2H-pyran-3-ylsulfanyl]-2-methyl-phenyl}-amide;and EXAMPLE 60 5-Trifluoromethyl-pyridine-2-sulfonic acid{5-tert-butyl-4-[4-hydroxy-6-isopropyl-2-oxo-6-(2-pyridin-3-yl-ethyl)-5,6-dihydro-2H-pyran-3-ylsulfanyl]-2-methyl-phenyl}-amide;EXAMPLE 613-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indol-5-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;EXAMPLE 623-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(2-methyl-thiophen-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;EXAMPLE 63(S)-3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(2-methyl-thiophen-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;EXAMPLE 643-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(3-methyl-thiophen-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;EXAMPLE 653-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(3-methyl-thiophen-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;EXAMPLE 663-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiophen-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;EXAMPLE 673-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(4-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;EXAMPLE 684-Hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-3-(5-isopropyl-benzothiazol-6-ylsulfanyl)-5,6-dihydro-pyran-2-one;EXAMPLE 694-Hydroxy-3-(6-tert-butyl-indol-5-ylsulfanyl)-6-[2-(2-hydroxymethyl-phenyl)-ethyl]6-isopropyl-5,6-dihydropyran-2-one;EXAMPLE 70(S)-N-[6-tert-Butyl-5-(4-hydroxy-6-isopropyl-2-oxo-6-[2-(4-hydroxy-phenyl)ethyl]-5,6-dihydro-2H-pyran-3-ylsulfanyl)-indolin-1-yl]-(4-cyanophenyl)sulfonamide;EXAMPLE 71(S)-6-tert-Butyl-5-{4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-indole-1-carboxylic acid tert-butyl ester; EXAMPLE 72(S)-3-(6-tert-Butyl-indol-5-yl-sulfanyl)-4-hydroxy6-[2-(4-hydroxy-phenyl)-ethyl]6-isopropyl-5,6-dihydro-pyran-2-one;EXAMPLE 73(S)-3-(6-tert-Butyl-1H-indol-5-yl-sulfanyl)-4-hydroxy-6-isopropyl-6-(2-phenethyl)-5,6-dihydro-pyran-2-one;EXAMPLE 74(S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;EXAMPLE 75(S)-4-Hydroxy-6-isopropyl-3-(6-isopropyl-3H-benzoimidazol-5-ylsulfanyl)-6-(2-phenethyl)-5,6-dihydro-pyran-2-one;EXAMPLE 76(S)-5-(4-Hydroxy-6-isopropyl-2-oxo-6-phenethyl-5,6-dihydro-2H-pyran-3-ylsulfanyl)-6-isopropyl-1,3-dihydro-benzoimidazol-2-one;EXAMPLE 77(S)-3-(6-tert-Butyl-3H-benzoimidazol-5-yl-sulfanyl)-4-hydroxy-6-isopropyl-6-(2-phenethyl)-5,6-dihydro-pyran-2-one;EXAMPLE 78(S)-5-tert-Butyl-6-(4-hydroxy-6-isopropyl-2-oxo-6-(2-phenethyl)-5,6-dihydro-2H-pyran-3-ylsulfanyl)-1,3-dihydro-benzoimidazol-2-one;EXAMPLE 79(S)-N-[5-tert-Butyl-6-(4-hydroxy-6-isopropyl-2-oxo-6-phenethyl-5,6-dihydro-2H-pyran-3-ylsulfanyl)-benzothiazol-2-yl]-methanesulfonamide;EXAMPLE 806-tert-Butyl-5-(4-hydroxy-6-isopropyl-2-oxo-6-phenethyl-5,6-dihydro-2H-pyran-3-ylsulfanyl)-1H-indole-2-carboxylicacid ethyl ester; EXAMPLE 816-tert-Butyl-5-(4-hydroxy-6-isopropyl-2-oxo-6-phenethyl-5,6-dihydro-2H-pyran-3-ylsulfanyl)-1H-indole-2-carboxylicacid; EXAMPLE 823-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-isopropyl-6-[(2-(3-thiophenyl)-ethyl)-5,6-dihydro-pyran-2-one;EXAMPLE 83(S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-[2-(3-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;EXAMPLE 843-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-[2-(3-fluoro-2-methyl-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;EXAMPLE 85(S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-[2-(3,5-difluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;EXAMPLE 86(S)-N-[5-tert-Butyl-6-(4-hydroxy-6-isopropyl-2-oxo-6-(2-phenethyl)-5,6-dihydro-2H-pyran-3-ylsulfanyl)-benzothiazol-2-yl]-acetamide;EXAMPLE 87(S)-N-{5-tert-Butyl-6-(4-hydroxy-6-isopropyl-2-oxo-6-(2-thiophen-3-yl-ethyl-5,6-dihydro-2H-pyran-3-ylsulfanyl)-benzothiazol-2-yl}-4-cyanobenzenesulfonamide;EXAMPLE 88(S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-[2-(4-fluoro-2-methyl-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;EXAMPLE 896-[2-(2-Amino-thiazol-4-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;EXAMPLE 90(S)-3-(6-tert-Butyl-2,3-dihydro-1H-indol-5-ylsulfanyl)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;EXAMPLE 91(S)-3-(6-tert-Butyl-2,3-dihydro-1H-indol-5-ylsulfanyl)-4-hydroxy-6-isopropyl-6-[(2-(3-thiophenyl)-ethyl)-5,6-dihydro-pyran-2-one;and EXAMPLE 924-(6-tert-Butyl-5-{4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-2,3-dihydro-indole-1-sulfonyl)-benzonitrile.

[1157] Other compounds which can be prepared by the above methodsinclude:

[1158]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(3-hydroxymethyl-thiophen-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[1159]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(3-methyl-thiophen-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[1160]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(2-methyl-thiophen-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[1161]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(4-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiophen-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[1162]3-(2-Cyclopentyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;

[1163]3-(4-Amino-2-cyclopentyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[1164]3-(4-Amino-2-cyclopentyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(4-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[1165]3-(6-tert-Butyl-1-hydroxy-indan-5-ylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;

[1166]3-(6-tert-Butyl-1-hydroxy-indan-5-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[1167]3-(6-tert-Butyl-1-hydroxy-indan-5-ylsulfanyl)-4-hydroxy-6-[2-(4-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[1168]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-furan-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[1169]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(3-hydroxymethyl-furan-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[1170]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(4-hydroxymethyl-furan-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[1171]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(2-methyl-furan-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[1172]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(3-methyl-furan-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[1173] 3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-furan-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[1174]3-(2-Cyclopentyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-6-(2-furan-3-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one,

[1175]3-(6-tert-Butyl-1-hydroxy-indan-5-ylsulfanyl)-6-(2-furan-3-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[1176]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(4-hydroxymethyl-thiazol-5-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[1177]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiazol-5-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[1178]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(5-hydroxymethyl-thiazol-4-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[1179]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(5-methyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[1180]6-[2-(2-Amino-thiazol-4-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[1181]6-[2-(2-Amino-thiazol-5-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[1182]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-isothiazol-4-yl-ethyl)-5,6-dihydro-pyran-2-one;

[1183]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-isothiazol-5-yl-ethyl)-5,6-dihydro-pyran-2-one;

[1184]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-isothiazol-3-yl-ethyl)-5,6-dihydro-pyran-2-one;

[1185]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-oxazol-5-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[1186]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indol-5-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[1187]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indol-5-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[1188]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indazol-5-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[1189]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indazol-5-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[1190]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-6-[2-(1H-benzoimidazol-5-yl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[1191]6-[2-(1H-Benzoimidazol-5-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[1192]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-6-[2-(3-amino-1H-indazol-5-yl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[1193]6-[2-(3-Amino-1H-indazol-5-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[1194]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indol-4-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[1195]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indol-4-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[1196]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indazol-4-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[1197]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indazol-4-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[1198]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-6-[2-(3-amino-1H-indazol-4-yl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[1199]6-[2-(3-Amino-1H-indazol-4-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[1200]3-(2-tert-Butyl-6-hydroxymethyl-5-methyl-pyridin-3-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[1201]3-(2-tert-Butyl-5-methyl-pyridin-3-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[1202]3-(3-tert-Butyl-2-hydroxymethyl-6-methyl-pyridin-4-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[1203]3-(5-tert-Butyl-2-methyl-pyridin-4-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[1204]3-(4-tert-Butyl-5-hydroxymethyl-thiophen-3-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[1205]3-(4-tert-Butyl-thiophen-3-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[1206]6-[2-(4-Amino-phenyl)-ethyl]-3-(2-tert-butyl-5-methyl-thiophen-3-ylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[1207]3-(2-tert-Butyl-5-methyl-thiophen-3-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[1208]6-[2-(4-Amino-phenyl)-ethyl]-3-(4-tert-butyl-5-hydroxymethyl-thiophen-3-ylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[1209]6-[2-(4-Amino-phenyl)-ethyl]-3-(3-tert-butyl-4-hydroxymethyl-5-methyl-thiophen-2-ylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[1210]3-(3-tert-Butyl-5-methyl-thiophen-2-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[1211]3-(3-tert-Butyl-4-hydroxymethyl-5-methyl-thiophen-2-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[1212]3-(3-tert-Butyl-4-hydroxymethyl-5-methyl-thiophen-2-ylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;

[1213]3-(6-tert-Butyl-2,3-dihydro-1H-indol-5-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[1214]3-(6-tert-Butyl-2,3-dihydro-1H-indol-5-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[1215]3-(6-tert-Butyl-1H-indol-5-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[1216]3-(6-tert-Butyl-1H-indol-5-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[1217]3-(7-tert-Butyl-1,2,3,4-tetrahydro-quinolin-6-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[1218]3-(7-tert-Butyl-1,2,3,4-tetrahydro-quinolin-6-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[1219]N-(7-tert-Butyl-6-{6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-4-methyl-benzothiazol-2-yl)-acetamide;

[1220]N-(7-tert-Butyl-6-{4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-4-methyl-benzothiazol-2-yl)-acetamide;

[1221]N-(7-tert-Butyl-6-{6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-4-methyl-benzothiazol-2-yl)-methanesulfonamide;

[1222]N-(7-tert-Butyl-6-{4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-4-methyl-benzothiazol-2-yl)-methanesulfonamide;

[1223]3-(7-tert-Butyl-2-dimethylamino-4-methyl-benzothiazol-6-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[1224]3-(7-tert-Butyl-2-dimethylamino-4-methyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[1225]3-(7-tert-Butyl-2-hydroxy-4-methyl-benzothiazol-6-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;

[1226]3-(7-tert-Butyl-2-hydroxy-4-methyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[1227]3-(2-tert-Butyl-6-hydroxymethyl-5-methyl-pyridin-3-ylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;

[1228]3-(3-tert-Butyl-2-hydroxymethyl-6-methyl-pyridin-4-ylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;

[1229] 3-(6-tert-Butyl-2.3-dihydro-1H-indol-5-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[1230]3-(6-tert-Butyl-1H-indol-5-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[1231]3-(7-tert-Butyl-1,2,3,4-tetrahydro-quinolin-6-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;

[1232]N-{7-tert-Butyl-6-[4-hydroxy-6-isopropyl-2-oxo-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-2H-pyran-3-ylsulfanyl]-4-methyl-benzothiazol-2-yl}-acetamide;

[1233]N-{7-tert-Butyl-6-[4-hydroxy-6-isopropyl-2-oxo-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-2H-pyran-3-ylsulfanyl]-4-methyl-benzothiazol-2-yl}-methanesulfonamide;

[1234]3-(7-tert-Butyl-2-dimethylamino-4-methyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-S,6-dihydro-pyran-2-one;

[1235]3-(7-tert-Butyl-2-hydroxy-4-methyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;

[1236](S)-3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-6-cyclohexyl-4-hydroxy-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;

[1237](S)-3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-6-cyclopentyl-4-hydroxy-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;

[1238](S)-3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-n-pentyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;

[1239]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-6-cyclohexyl-4-hydroxy-6-(2-thiophen-2-yl-ethyl)-5,6-dihydro-pyran-2-one;

[1240]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-6-cyclopentyl-4-hydroxy-6-(2-thiophen-2-yl-ethyl)-5,6-dihydro-pyran-2-one;

[1241]3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-n-pentyl-6-(2-thiophen-2-yl-ethyl)-5,6-dihydro-pyran-2-one;

[1242]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-6-cyclohexyl-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[1243]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-6-cyclopentyl-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;

[1244]3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-n-pentyl-5,6-dihydro-pyran-2-one;

[1245](S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-n-pentyl-6-phenethyl-5,6-dihydro-pyran-2-one;

[1246](S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-cyclohexyl-4-hydroxy-6-phenethyl-5,6-dihydro-pyran-2-one;

[1247](S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-cyclopentyl-4-hydroxy-6-phenethyl-5,6-dihydro-pyran-2-one;

[1248](S)-4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-propyl-3-(5-isopropyl-benzothiazol-6-ylsulfanyl)-5,6-dihydro-pyran-2-one;

[1249](S)-6-Cyclohexyl-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-3-(5-isopropyl-benzothiazol-6-ylsulfanyl)-5,6-dihydro-pyran-2-one;

[1250](S)-6-Cyclopentyl-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-3-(5-isopropyl-benzothiazol-6-ylsulfanyl)-5,6-dihydro-pyran-2-one;

[1251](S)-3-(6-tert-Butyl-1H-indol-5-yl-sulfanyl)-4-hydroxy-6-propyl-6-(2-phenethyl)-5,6-dihydro-pyran-2-one;

[1252](S)-3-(6-tert-Butyl-1H-indol-5-yl-sulfanyl)-6-cyclohexyl-4-hydroxy-6-(2-phenethyl)-5,6-dihydro-pyran-2-one;

[1253](S)-3-(6-tert-Butyl-1H-indol-5-yl-sulfanyl)-6-cyclopentyl-4-hydroxy-6-(2-phenethyl)-5,6-dihydro-pyran-2-one;

[1254](S)-3-(6-tert-Butyl-1H-indol-5-yl-sulfanyl)-4-hydroxy-6-pentyl-6-(2-phenethyl)-5,6-dihydro-pyran-2-one;

[1255](S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-[2-(3-fluoro-phenyl)-ethyl]-4-hydroxy-6-propyl-5,6-dihydro-pyran-2-one;

[1256](S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-[2-(3-fluoro-phenyl)-ethyl]-4-hydroxy-6-pentyl-5,6-dihydro-pyran-2-one;

[1257](S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-cyclohexyl-6-[2-(3-fluoro-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;and

[1258](S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-cyclopentyl-6-[2-(3-fluoro-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one.

[1259] The compounds of the present invention were evaluated for theirin vitro inhibition of HIV protease and for their antiviral efficacy inHIV infected lymphocytes and the results shown in Table 1. Two referenceagents are included and are shown below.

[1260] The two Reference Agents 1 and 2 are the two best compounds asdisclosed by Hagen, et al. J. Med. Chem., 1997;40:3707-3711). Thesereference compounds were recognized to have particularly good antiviralactivity due in part to the polar substituents placed on the phenyl andphenethylmoieties. In a subsequent disclosure by S. Vander Roest, etal., 37^(th) Interscience Conference on Antimicrobial Agents andChemotherapy, Sep. 28-Oct. 1, 1997. Toronto, Canada Abstract 1-84), itwas revealed that Reference Agents 1 and 2 had comparatively goodpharmacokinetics in mice relative to a large series of related polarsubstituted phenyl and phenethyl derivatives. Thus, Reference Agents 1and 2, represent excellent comparative agents for the compounds of thecurrent invention both in vitro and in vivo.

[1261] The following sections provide the experimental methodology forthe in vitro and in vivo assays employed to demonstrate the efficacy andadvantages of the compounds of the current invention.

[1262] HIV Protease Assay:

[1263] Materials

[1264] Recombinant HIV-1 protease (>96% purity) and HIV proteasesubstrate III (the undecapeptideH-His-Lys-Ala-Arg-Val-Leu-Nph-Glu-Ala-Nle-Ser-NH₂, 97% purity) werepurchased from Bachem Bioscience, Inc. (King of Prussia, Pa.).

[1265] Method

[1266] The methods employed follow the procedures of Tummino, et al.,Archives of Biochemistry and Biophysics, 1995;316:523). Fordetermination of Ki values, HIV-1 protease, 6.0 nM final concentration,was added to a solution containing inhibitor, 40 μM substrate III and1.0% Me₂SO in assay buffer: 80 mM MES, 160 mM NaCl, 1.0 mM EDTA 0.1%polyethylene glycol (Mr 8000) pH 6.2 at 37° C. (total volume, 100 & 1).Polyethylene glycol was used in the assay in place of glycerol since theformer was reported to be a more effective stabilizing agent in theprotease (Jordan, et al., J. Biol. Chem., 1992;267:20028). The finalinhibitor concentrations used were 0 (0.1, 0.2, in some experiments),0.5, 1, 2, 5, 10, 20, 50, and 100 μM. The solution was mixed, incubatedfor 5 minutes and the reaction quenched by addition of trifluoraceticacid. 2% final. The (leu-p-nitro-phe) bond of the substrate is cleavedby the enzyme and substrate and products separated by reverse-phaseHPLC. Absorbance was measured at 220 nm, peak areas determined, andpercentage conversion to product used to calculate percentage control(=[% conversion (+inhibitor)/% conversion (−inhibitor)]×100).

[1267] Cellular Infection Assay

[1268] Compounds were tested in lymphocyte derived CEM cells using theXTT cytopathic procedures and were performed at Southern ResearchInstitute (Buckheit, et al., Antiviral Res., 1993;21:247; see alsoWeislow, et al. J. Nat. Cancer Inst., 1989;81:577). Compoundconcentrations were 0.32, 1, 3.2.10.32 and 100 uM. The EC₅₀ representsthe concentration of agent which reduces HIV cytopathic effects 50%relative to untreated control. Cellular toxicity of the agents areestimated from the TC₅₀ which represents the concentration of the agentwhich inhibits 50% of the viability of uninfected cells.

[1269] Table 1 contains the results of the HIV protease assay Ki and theantiviral efficacy (EC₅₀, TC₅₀, TI) screening, where TI is thetherapeutic index (TC₅₀/EC₅₀).

[1270] Mouse Blood Levels

[1271] Charles River CD-1 mice were dosed with a 25 mg/kg drug solutionorally by gavage. For oral dosing the compounds were dissolved in 0.1NNaOH (20% final volume) and then 0.5% methylcellulose (80% final volume)was added. Blood was drawn and pooled from 5 mice at each time point viaheart puncture and was placed in a 15 mL centrifuge tube containingheparin. The plasma stored in 200 μL aliquots at −80° C. until assayed.

[1272] Plasma was thawed at room temperature and then 400 μL ofacetonitrile was added to each vial and vortexed. Followingcentrifugation the supernatant was removed and evaporated in a nitrogenevaporator at 48° C. Residue was then resolublized in 200 μL of a 75%water/25% CH₃CN solution for HPLC analysis. HPLC analysis used a ZorbaxRX-C8 column (4.6×150 mm) with a 25 mM potassium phosphate buffer with0.1% TFA, pH 3.0. Mobile phases consisted of varying percentages of twobuffer mixtures: Buffer A—90% buffer, 10% CH₃CN, and Buffer B—30%buffer, 70% CH₃CN. Absorbance was determined at a wavelength of 260 nM.

[1273] A standard curve ranging from 0.5 to 50 μg/mL was used for eachdrug tested. Ten times final concentration solutions of drug in waterwere prepared from stock solutions of 1 mg/mL drug in DMSO. The final1:10 dilution was then done in mouse plasma obtained from mice describedabove.

[1274] The results from testing the reference agents and the compoundsof this invention are shown in Table 2.

[1275] Rat and Dog Blood Levels

[1276] The procedure for pharmacokinetic analysis in dogs and rats wassimilar. For dog studies, two dogs received a single oral 10 mg/kg doseof the HIV protease inhibitor as a solution. The protease inhibitor wasdissolve in 0.1N NaOH followed by buffering or diluting with isotonicphosphate buffer or water depending on solubility. For rat studies, twomale rats received a single oral 10 mg/kg gavage dose of the HIVprotease inhibitor suspended in 0.5% methylcellulose. For the IVadministration, the compounds were dissolved in 0.1N sodium hydroxide ata concentration of 10 mg/ml. The IV dose was given bolus. Blood sampleswere collected prior to dosing and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 8, 12,and 24 hours postdose. Plasma samples were analyzed for the HIV proteaseinhibitor using a HPLC procedure. The method involved plasma proteinprecipitation with acetonitrile, reverse-phase chromatographicseparation of the HIV protease inhibitor and internal standard, andquantitation by UV detection. Some plasma samples were concentrated byevaporation prior to injection. Pharmacokinetic parameters weredetermined by noncompartmental analysis of individual rat-plasmaconcentration-time curves using WinNonlin. Maximum concentration (Cmax)and time for these to occur (tmax) were recorded as observed. Area underconcentration-time curve (AUC) values were obtained using the lineartrapezoidal rule. The results of the pharmacokinetic studies in dogs andrats are shown in Table 3.

[1277] Table 1 indicates that the compounds of the present inventionhave good to excellent activity toward inhibiting the HIV proteaseenzyme (Ki's) as well as activity in HIV infected cells, protecting thecells from HIV pathogenicity at μM and sub-μM concentrations. The tworeference agents in Table 1, which represent the best of thehydroxylated and aminated compounds from the art, are wholly comparableto the compounds of the current invention at the antiviral level. Yetthe current invention relies not only on the antiviral activity but onthe unexpected finding that certain heterocycles could sufficientlymimic the polar groups of the reference agents while effectingsignificant gains in pharmacokinetic parameters due in part to reducedmetabolism of the amines and phenols of the reference agents.

[1278] In Table 2, the results from mouse pharmacokinetic studies areshown for the reference agents and certain of the compounds of thepresent invention. In Table 3, the oral pharmacokinetics of certaincompounds and the reference agents in rats and dogs are shown. Table 4shows the pharmacokinetics in rats compared to the reference agents.

[1279] The results in Table 2 show a clear improvement in Cmax and T1/2of the compounds of the invention relative to the Reference Agents. Theresults from Table 3 show that the pharmacokinetic advantages of thecompounds of the current invention are not limited to mice but aremanifest in rats and dogs. Such data all support the unexpectedobservation that select heterocycles mimic the polar hydroxylated andaminated phenyl groups, yet posses unexpectedly good pharmacokineticsrelative to the best Reference Agents. TABLE 1 Inhibition ofHIV-Protease and Antiviral Efficacy in a CEM Cell Infection Assay Inhibof HIV Antiviral Efficacy Example Protease KI (nM) EC₅₀ (μM) TC₅₀ (μM)TI 1 1.5 1.5 296 197 2 0.9 0.9 216 240 4 0.35 1.0 199 199 5 0.78 0.75190 253 7 0.17 0.3 110 366 8 0.35 0.5 80.5 161 9 0.19 1.8 210 117 110.23 0.29 133 458 12 0.07 0.14 91 650 13 0.28 42 152 14 0.67 2.5 75 3016 11 114 10.4 17 2.7 42 16 18 1.1 117 105 22 0.85 1.5 66 43 24 0.37 164443 25 0.57 0.7 216 308 26 0.45 0.8 171 213 28 0.24 1.9 229 120 32 1.623 91 4 33 1.4 101 72 35 0.88 1.5 72 48 36 1.7 2.2 170 77 37 0.37 4.2100 24 38 0.33 1.1 124 113 40 0.28 5.6 >320 >57 41 6.5 20 195 10 421.3 >200 >159 48 0.4 0.37 29 78 55 1.7 8.3 66 8 56 11 10 210 21 59 0.080.6 66 110 61 0.98 0.68 46 68 65 1.2 1.1 60 54 69 0.67 0.18 55 306 700.82 1.3 8 6 73 0.54 0.61 42 69 79 2.1 2.2 125 56 82 1.1 0.7 76 109 830.44 0.26 61 235 84 0.8 0.47 93 198 89 0.95 3.5 >200 >57 Ref 1 0.430.5 >100 >200 Ref 2 0.22 0.6 >100 >166

[1280] TABLE 2 Pharmacokinetic Evaluation of HIV Protease Inhibitors inMice Following an Oral Dose of 25 mg/kg Cmax^(a) T ½^(b) Example (μM)(hr) Ref 1 23 2.2 Ref 2 17 2.0 2 46 7.3 4 54 5.6 7 40 3.5 12 95 9.5 2533 3.3

[1281] TABLE 3 Pharmacokinetic Evaluation of HIV Protease Inhibitors inRats and Dogs Following an Oral Dose of 10 mg/kg Rats Dogs Cmax^(a) T½^(b) Cmax T ½^(b) Example (μM) (hr) (μM) (hr) Ref 1 16 3.4 140 1.25 Ref2 3.4 0.55  40 0.52 12 30 11.5 149 1.75 13 5.1 8.6 — — 25 6.0 12.0 — —

[1282] TABLE 4 Pharmacokinetic Evaluation of HIV Protease Inhibitors inRats Following an IV Dose of 10 mg/kg C(0) T ½^(a) Example (μM) (hr) Ref1 86 3.7 Ref 2 100 3.9 12 160 12.0 25 120 8.0 69 335 4.5 83 199 4.0

1. A compound of Formula I

or a pharmaceutically acceptable salt thereof wherein R₁ is H, astraight or branched alkyl of 1-6 carbons or a carbocycle of 3-6carbons; R₂ is H, a straight or branched alkyl of 1-5 carbons; R₃ is H,(CR′₂)_(n)OR, (CR′₂)_(n)N(R)₂, (CR′₂)_(n)NR′COR, (CR′₂)_(n)CO₂R,(CR′₂)_(n)OCOR, (CR′₂)_(n)CON(R)₂, (CR′₂)_(n)OCON(R)₂, (CR′₂)_(n)R,(CR′₂)_(n)NR′CON(R)₂, (CR′₂)_(n)NR′CO₂R, (CR′₂)_(n)OSO₂N(R)₂,(CR′₂)_(n)NR′SO₂OR, (CR′₂)_(n)NR′SO₂N(R)₂, (CR′₂)_(n)OSO₂R,(CR′₂)_(n)NR′SO₂R, (CR′₂)_(n)SO_(p)R, (CR′₂)_(n)NR′CSN(R)₂,(CR′₂)_(n)NR′C(NR′)N(R)₂, (CR′₂)_(n)SO₂N(R)₂, (CR′₂)_(n)C(NR′)N(R)₂,(CR′₂)_(n)COR, O(CR′₂)_(m)OR, NR(CR′₂)_(m)OR, F, Cl, Br, CF₃, CN, or ═O;R₄, R₅, and R₆ are independently H, a straight or branched alkyl of 1-6carbons, a cycloalkyl of 3-6 carbons, (CR′₂)_(n)OR, (CR′₂)_(n)N(R)₂, F,Cl, Br, CN, CF₃, ═O, (CR′₂)_(p)NR′COR, (CR′₂)_(p)SO_(p)R, (CR′₂)_(p)R,(CR′₂)_(p)OCOR, O(CR′₂)_(m)OR, NR(CR′₂)_(m)OR, (CR′₂)_(p)NR′CON(R)₂,(CR′₂)_(p)OCON(R)₂, (CR′₂)_(p)NR′CO₂R, (CR′₂)_(p)COR, (CR′₂)_(p)CO₂R,(CR′₂)_(p)CON(R)₂, (CR′₂)_(p)NR′SO₂R(CR′₂)_(p)SO₂N(R)₂, (CR′₂)_(p)NR′SO₂OR, (CR′₂)_(p)OSO₂N(R)₂, (CR′₂)_(p)NR′SO₂N(R)₂, (CR′₂)_(p)C(NR′)N(R)₂,(CR′₂)_(p)NR′C(NR′)N(R)₂, (CR′₂)_(p)Het; any two of R₁—R₃ or R₄-R₆ maytogether form a ring of 5-6 total atoms which may contain 0-3heteroatoms; n is an integer of from 0 to 3; m is an integer of from 2to 4; p is an integer from 0 to 2; R₇ is a straight or branched alkyl of1-6 carbons or a carbocycle of 3-6 carbons; R is independently H, astraight or branched alkyl of 1-4 carbons, (CH₂)_(n)Ph, or a(CH₂)_(n)heterocycle of 5-6 atoms containing 1-2 heteroatoms and whereinthe (R)₂ in N(R)₂ may form a heterocycle containing the nitrogen, alloptionally substituted by F, Cl, Br, OR′, CN, CO₂R′, N(R′)₂, NR′COR′,CF₃, or ═O; R′ is independently H, a straight or branched alkyl of 1-4carbons, or phenyl; R″ is independently H, a straight or branched alkylof 1-4 carbons, F, Cl, Br, OR′, or N(R′)₂; Ar₁ and Ar₂ are independentlyphenyl or Het with the proviso that at least one Ar is Het; Het is aheterocycle of from 5-6 atoms having from 1-4 heteroatoms or a fusedheterocycle of from 9-10 atoms having 1-3 heteroatoms.
 2. A compoundaccording to claim 1 wherein: R₁ is a straight or branched alkyl of from1 to 4 carbons or a carbocycle of from 3 to 5 carbons and R₂ is H or astraight or branched alkyl of from 1 to 3 carbons.
 3. A compoundaccording to claim 1 wherein: R₁ is isopropyl or t-butyl; R₂ is H,methyl, or ethyl; R₃ is H, (CR′₂)_(n)OR, (CR′₂)_(n)N(R)₂,(CR′₂)_(n)NR′COR, (CR′₂)_(n)CO₂R, (CR′₂)_(n)OCOR, (CR′₂)_(n)CON(R)₂,(CR′₂)_(n)OCON(R)₂, (CR′₂)_(n)NR′CON(R)₂, (CR′₂)_(n)NR′CO₂R,(CR′₂)_(n)OSO₂N(R)₂, (CR′₂)_(n)NR′SO₂OR, (CR′₂)_(n)NR′SO₂N(R)₂(CR′₂)_(n)OSO₂R, (CR′₂)_(n)NR′SO₂R, (CR′₂)_(n)SO_(p)R,(CR′₂)_(n)NR′CSN(R)₂, (CR′₂)_(n)COR, O(CR′₂)_(m)OR, NR(CR′₂)_(m)OR, F,Cl, Br, CF₃, CN, or ═O; R₄, R₅, and R₆ are independently H, a straightor branched alkyl of 1-6 carbons, a cycloalkyl of 3-6 carbons.(CH₂)_(n)OR, (CH₂)_(n)N(R)₂, F, Cl, Br, CN, CF₃, ═O, (CR′₂)_(p)NR′COR,(CR′₂)_(p)SO_(p)R, (CR′₂)_(p)NR′CON(R)₂, (CR′₂)_(p)OCON(R)₂,(CR′₂)_(p)NR′CO₂R, (CR′₂)_(p)COR, (CR′₂)_(p)CO₂R, (CR′₂)_(p)CON(R)₂,(CR′₂)_(p)NR′SO₂R, (CR′₂)_(p)SO₂N(R)₂, (CR′₂)_(p)NR′SO₂OR,(CR′₂)_(p)OSO₂N(R)₂, (CR′₂)_(p)Het and any two of R₁—R₃ or R₄-R₆ maytogether form a ring of 5-6 total atoms which may contain 0-2heteroatoms; n is an integer of 0 to 3; m is an integer of 2 to 4; p is0 to 2; R₇ is a straight or branched alkyl of 1-6 carbons or acarbocycle of 3-6 carbons; R is H, a straight or branched alkyl of 1-4carbons, (CH₂)_(n)Ph, or a (CH₂)_(n)heterocycle of 5-6 atoms containing1-2 heteroatoms and wherein the (R)₂ in N(R)₂ may form a heterocyclecontaining the nitrogen, all optionally substituted by F, Cl, Br, OR′,N(R′)₂, NR′COR′, CF₃, or ═O; R′ is H, a straight or branched alkyl of1-4 carbons, or phenyl; R″ is H, a straight or branched alkyl of 1-4carbons, F, Cl, Br, OR′, or N(R′)₂; Ar₁ is phenyl or Het; and Ar₂ is Hetwherein Het is a heterocycle of from 5-6 atoms having 1-4 heteroatomsselected from: furan, pyrrole, thiophene, oxazole, isoxazole, thiazole,pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine,pyridazine, pyrimidine, pyrazine, tetrahydrofuran, tetrahydrothiophene,pyrrolidine, piperazine, piperidine, morpholine, thiomorpholine,oxolane, dioxane, sulfolane; or a fused heterocycle of from 9-10 atomshaving from 1-3 heteroatoms selected from: benzofuran, indole, indoline,benzothiophene, benzimidazole, benzthiazole, benzoxazole, quinoline,isoquinoline, cinnoline, quinazoline and quinoxaline.
 4. A compoundaccording to claim 1 wherein: R₁ is isopropyl or t-butyl; R₂ is H,methyl or ethyl; R₃ is H, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, (CH₂)_(n)NR′COR,(CH₂)_(n)CON(R)₂, (CH₂)_(n)OCON(R)₂, (CH₂)_(n)NR′CON(R)₂,(CH₂)_(n)NR′CO₂R, (CH₂)_(n)OSO₂N(R)₂, (CH₂)_(n)NR′SO₂OR,(CH₂)_(n)NR′SO₂N(R)₂, (CH₂)_(n)OSO₂R, (CH₂)_(n)NR′SO₂R, (CH₂)_(n)SO₂R,(CH₂)_(n)NR′CSN(R)₂, (CH₂)_(n)COR, O(CH₂)_(m)OR′, NR(CH₂)_(m)OR′, orC(CH₃)₂OR′; R₄, R₅, and R₆ are independently H, a straight or branchedalkyl of 1-6 carbons, a cycloalkyl of 3-6 carbons, (CH₂)_(n)OR,(CH₂)_(n)N(R)₂, F, Cl, Br, CN, CF₃, ═O, (CH₂)_(p)NR′COR,(CH₂)_(p)NR′CON(R)₂, (CH₂)_(p)OCON(R)₂, (CH₂)_(p)NR′CO₂R, (CH₂)_(p)COR,(CH₂)_(p)CON(R)₂, (CH₂)_(p)NR′SO₂R, (CH₂)_(p)NR′SO₂OR,(CH₂)_(p)OSO₂N(R)₂, wherein p is 0 to 2, or R₄ and R₅ may together forma ring of 5-6 total atoms which may contain 0-2 heteroatoms; n is aninteger of 0 to 3; m is an integer of 2 to 4; R₇ is a straight orbranched alkyl of 1-6 carbons or a carbocycle of 3-6 carbons; R is H, astraight or branched alkyl of 1-4 carbons, (CH₂)_(n)Ph, or a(CH₂)_(n)heterocycle of 5-6 atoms containing 1-2 heteroatoms and whereinthe (R)₂ in N(R)₂ may be a heterocycle containing the nitrogen, alloptionally substituted by F, Cl, Br, OR′, N(R′)₂, NR′COR′, or ═O; R′ isH, a straight or branched alkyl of 1-4 carbons, or phenyl; R″ is H, astraight or branched alkyl of 1-4 carbons, F, Cl, Br, OR′, or N(R′)₂;Ar₁ is phenyl; and Ar₂ is a heterocycle of 5-6 atoms having from 1-4heteroatoms selected from: furan, pyrrole, thiophene, oxazole,isoxazole, thiazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole,tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, tetrahydrofuran,tetrahydrothiophene, pyrrolidine, piperazine, piperidine, morpholine,thiomorpholine, oxolane, dioxane, sulfolane; or a fused heterocycle of9-10 atoms having from 1-3 heteroatoms selected from: benzofuran,indole, indoline, benzothiophene, benzimidazole, benzthiazole,benzoxazole, quinoline, isoquinoline, cinnoline, quinazoline andquinoxaline.
 5. A compound according to claim 1 wherein: R₁ is H, astraight or branched alkyl of 1-6 carbons or a carbocycle of 3-6carbons; R₂ is H, a straight or branched alkyl of 1-5 carbons; R₃ is H,(CH₂)_(n)OR, (CH₂)_(n)N(R)₂, (CH₂)_(n)NR′COR, (CH₂)_(n)CON(R)₂,(CH₂)_(n)OCON(R)₂, (CH₂)_(n)NR′CON(R)₂ (CH₂)_(n)NR′CO₂R,(CH₂)_(n)OSO₂N(R)₂, (CH₂)_(n)NR′SO₂OR, (CH₂)_(n)NR′SO₂N(R)₂,(CH₂)_(n)OSO₂R, (CH₂)_(n)NR′SO₂R, (CH₂)_(n)SO₂R, (CH₂)_(n)COR,O(CH₂)_(m)OR, NR(CH₂)_(m)OR′, C(CH₃)₂OR′, F, Cl, Br, CF₃, or ═O; R₄, R₅,and R₆ are independently H, a straight or branched alkyl of 1-6 carbons,a cycloalkyl of 3-6 carbons, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, F, Cl, Br, ═O,(CH₂)_(p)NR′COR, (CH₂)_(p)NR′CON(R)₂, (CH₂)_(p)OCON(R)₂,(CH₂)_(p)NR′CO₂R, (CH₂)_(p)COR, (CH₂)_(p)CON(R)₂, (CH₂)_(p)NR′SO₂R,(CH₂)_(p)NR′SO₂OR, (CH₂)_(p)OSO₂N(R)₂, wherein p is 0 to 2; R₄ and R₅may together form a ring of 5-6 total atoms which may contain 0-2heteroatoms; n is an integer of 0 to 3; m is an integer of 2 to 4; R₇ ismethyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl; R is H, a straight or branched alkyl of 1-4 carbons,(CH₂)_(n)Ph, or a (CH₂)_(n)heterocycle of 5-6 atoms containing 1-2heteroatoms and wherein the (R)₂ in N(R)₂ may be a heterocyclecontaining the nitrogen, all optionally substituted by F, Cl, Br, OR′,N(R′)₂, NR′COR′, or ═O; R′ is H, a straight or branched alkyl of 1-4carbons, or phenyl; R″ is H, a straight or branched alkyl of 1-4carbons, F, Cl, Br, OR′, or N(R′)₂; Ar₁ is phenyl or Het; and Ar₂ is Hetwherein Het is a heterocycle of 5-6 atoms having from 1-4 heteroatomsselected from: furan, pyrrole, thiophene, oxazole, isoxazole, thiazole,pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine,pyridazine, pyrimidine, pyrazine, tetrahydrofuran, tetrahydrothiophene,pyrrolidine, piperazine, piperidine, morpholine, thiomorpholine,oxolane, dioxane, sulfolane; or a fused heterocycle of from 9-10 atomshaving 1-3 heteroatoms selected from: benzofuran, indole, indoline,benzothiophene, benzimidazole, benzthiazole, benzoxazole, quinoline,isoquinoline, cinnoline, quinazoline and quinoxaline.
 6. A compoundaccording to claim 1 wherein: R₁ is H, methyl, ethyl, isopropyl, ort-butyl; R₂ is H or methyl; R₃ is H, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂,(CH₂)_(n)NR′COR, (CH₂)_(n)CON(R)₂, (CH₂)_(n)OCON(R)₂,(CH₂)_(n)NR′CON(R)₂, (CH₂)_(n)NR′CO₂R, (CH₂)_(n)OSO₂N(R)₂,(CH₂)_(n)NR′SO₂OR, (CH₂)_(n)NR′SO₂N(R)₂, (CH₂)_(n)OSO₂R,(CH₂)_(n)NR′SO₂R, (CH₂)_(n)SO₂R, (CH₂)_(n)COR, O(CH₂)_(m)OR′,NR(CH₂)_(m)OR′, C(CH₃)₂OR′, F, Cl, Br, CF₃, or ═O; R₄, R₅, and R₆ areindependently H, a straight or branched alkyl of 1-6 carbons, acycloalkyl of 3-6 carbons, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, F, Cl, Br, CF₃,(CH₂)_(p)NR′COR, (CH₂)_(p)NR′CON(R)₂, (CH₂)_(p)OCON(R)₂,(CH₂)_(p)NR′CO₂R, (CH₂)_(p)COR, (CH₂)_(p)CON(R)₂, (CH₂)_(p)NR′SO₂R,(CH₂)_(p)NR′SO₂OR, (CH₂)_(p)OSO₂N(R)₂, (CH₂)_(p)Het wherein p is 0 to 2;any two of R₄-R₆ may together form a ring of 5-6 total atoms which maycontain 0-2 heteroatoms; n is an integer of 0 to 3; m is an integer of 2to 4; R₇ is a straight or branched alkyl of 1-6 carbons or a carbocycleof 3-6 carbons; R is H, a straight or branched alkyl of 1-4 carbons,(CH₂)_(n)Ph, or a (CH₂)_(n)heterocycle of 5-6 atoms having from 1-2heteroatoms and wherein the (R)₂ in N(R)₂ may form a heterocycle havingnitrogen, all optionally substituted by F, Cl, Br, OR′, N(R′)₂, NR′COR′,or ═O; R′ is H, a straight or branched alkyl of 1-4 carbons, or phenyl;R″ is H, a straight or branched alkyl of 1-4 carbons, F, Cl, Br, OR′, orN(R′)₂; Ar₁ is a heterocycle of 5-6 atoms having from 1-4 heteroatomsselected from: furan, pyrrole, thiophene, oxazole, isoxazole, thiazole,pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine,pyridazine, pyrimidine, pyrazine, tetrahydrofuran, tetrahydrothiophene,pyrrolidine, piperazine, piperidine, morpholine, thiomorpholine,oxolane, dioxane, sulfolane; or a fused heterocycle of 9-10 atoms having1-3 heteroatoms selected from: benzofuran, indole, indoline,benzothiophene, benzimidazole, benzthiazole, benzoxazole, quinoline,isoquinoline, cinnoline, quinazoline and quinoxaline; and Ar₂ is phenyl.7. A compound according to claim 1 wherein: R₁ is isopropyl or t-butyl;R₂ is H or methyl; R₃ is H, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂,(CH₂)_(n)OCON(R)₂, (CH₂)_(n)NR′CON(R)₂, (CH₂)_(n)NR′CO₂R,(CH₂)_(n)OSO₂N(R)₂, (CH₂)_(n)NR′SO₂OR, (CH₂)_(n)NR′SO₂N(R)₂,(CH₂)_(n)NR′SO₂R, (CH₂)_(n)SO₂R, O(CH₂)_(m)OR′, NR(CH₂)_(m)OR′, orC(CH₃)₂OR′; R₄, R₅, and R₆ are independently H, a straight or branchedalkyl of 1-6 carbons, a cycloalkyl of 3-6 carbons, (CH₂)_(n)OR,(CH₂)_(n)N(R)₂, F, Cl, Br, ═O, (CH₂)_(p)NR′COR, (CH₂)_(p)NR′CON(R)₂,(CH₂)_(p)OCON(R)₂, (CH₂)_(p)NR′CO₂R, (CH₂)_(p)COR, (CH₂)_(p)CON(R)₂,(CH₂)_(p)NR′SO₂R, (CH₂)_(p)NR′SO₂OR, (CH₂)_(p)OSO₂N(R)₂, wherein p is 0to 2; R₄ and R₅ may together form a ring of 5-6 total atoms which maycontain 0-2 heteroatoms; n is an integer of 0 to 3; m is an integer of 2to 4; R₇ is a straight or branched alkyl of 1-6 carbons or a carbocycleof 3-6 carbons; R is H, a straight or branched alkyl of 1-4 carbons,(CH₂)_(n)Ph, or a (CH₂)_(n)heterocycle of 5-6 atoms having from 1-2heteroatoms and wherein the (R)₂ in N(R)₂ may be a heterocyclecontaining the nitrogen, all optionally substituted by F, Cl, Br, OR′,N(R′)₂, NR′COR′, or ═O; R′ is H, a straight or branched alkyl of 1-4carbons, or phenyl; R″ is H, a straight or branched alkyl of 1-4carbons, F, Cl, Br, OR′, or N(R′)₂; Ar₁ is phenyl; and Ar₂ is furan,pyrrole, thiophene, oxazole, isoxazole, thiazole, pyrazole, tetrazole,or pyridine.
 8. A compound according to claim 1 wherein: R₁ is H, astraight or branched alkyl of 1-6 carbons or a carbocycle of 3-6carbons; R₂ is H, methyl or ethyl or isopropyl; R₃ is H, (CH₂)_(n)OR,(CH₂)_(n)N(R)₂, (CH₂)_(n)NRCOR, (CH₂)_(n)CON(R)₂, (CH₂)_(n)OCON(R)₂,(CH₂)_(n)NR′CON(R)₂, (CH₂)_(n)NR′CO₂R, (CH₂)_(n)OSO₂N(R)₂,(CH₂)_(n)NR′SO₂OR, (CH₂)_(n)NR′SO₂N(R)₂, (CH₂)_(n)OSO₂R,(CH₂)_(n)NR′SO₂R, (CH₂)_(n)SO₂R, O(CH₂)_(m)OR, NR(CH₂)_(m)OR′,C(CH₃)₂OR′, or ═O; R₄, R₅, and R₆ are independently H, a straight orbranched alkyl of 1-6 carbons, a cycloalkyl of 1-6 carbons, (CH₂)_(n)OR,(CH₂)_(n)N(R)₂, F, Cl, Br, ═O, (CH₂)_(p)NR′COR, (CH₂)_(p)NR′CON(R)₂,(CH₂)_(p)OCON(R)₂, (CH₂)_(p)NR′CO₂R, (CH₂)_(p)COR, (CH₂)_(p)CON(R)₂,(CH₂)_(p)NR′SO₂R, (CH₂)_(p)NR′SO₂OR, (CH₂)_(p)OSO₂N(R)₂, wherein p is 0to 2; R₄ and R₅ may together form a ring of 5-6 total atoms which maycontain 0-2 heteroatoms; n is an integer of 0 to 3; m is an integer of 2to 4; R₇ is a straight or branched alkyl of 1-6 carbons or a carbocycleof 3-6 carbons; R is H, a straight or branched alkyl of 1-4 carbons,(CH₂)_(n)Ph, or a (CH₂)_(n)heterocycle of 5-6 atoms containing 1-2heteroatoms and wherein the (R)₂ in N(R)₂ may be a heterocycle havingnitrogen, all optionally substituted by F, Cl, Br, OR′, N(R′)₂, NR′COR′,or ═O; R′ is H, a straight or branched alkyl of 1-4 carbons, or phenyl;R″ is H, a straight or branched alkyl of 1-4 carbons, F, Cl, Br, OR′, orN(R′)₂; Ar₁ is thiophene, thiazole, pyridine, benzothiophene,benzthiazole, benzoxazole, quinoline or isoquinoline; and Ar₂ is phenylor Het wherein Het is a heterocycle of 5-6 atoms having from 1-4heteroatoms selected from: furan, pyrrole, thiophene, oxazole,isoxazole, thiazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole,tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, tetrahydrofuran,tetrahydrothiophene, pyrrolidine, piperazine, piperidine, morpholine,thiomorpholine, oxolane, dioxane, sulfolane; or a fused heterocycle of9-10 atoms having 1-3 heteroatoms selected from: benzofuran, indole,indoline, benzothiophene, benzimidazole, benzthiazole, benzoxazole,quinoline, isoquinoline, cinnoline, quinazoline and quinoxaline.
 9. Acompound according to claim 1 wherein: R₁ is isopropyl or t-butyl; R₂ isH, methyl, or ethyl; R₃ is CH₂OH, NH₂, OCH₂CH₂OH, NHCOR, OSO₂N(R)₂,NR′SO₂OR, NR′SO₂R, or OSO₂R; R₄, R₅ and R₆ are independently H, astraight or branched alkyl of 1-6 carbons, a cycloalkyl of 1-6 carbons,(CH₂)_(n)OR, (CH₂)_(n)N(R)₂, F, Cl, Br, ═O, (CH₂)_(p)NR′COR,(CH₂)_(p)NR′CON(R)₂, (CH₂)_(p)OCON(R)₂, (CH₂)_(p)NR′CO₂R, (CH₂)_(p)COR,(CH₂)_(p)CON(R)₂, (CH₂)_(p)NR′SO₂R, (CH₂)_(p)NR′SO₂OR,(CH₂)_(p)OSO₂N(R)₂, wherein p is 0 to 2; R₄ and R₅ may together form aring of 5-6 total atoms which may contain 0-2 heteroatoms; R₇ is astraight or branched alkyl of 1-6 carbons or a carbocycle of 3-6carbons, R is H, a straight or branched alkyl of 1-4 carbons,(CH₂)_(n)Ph, or a (CH₂)_(n)heterocycle of 5-6 atoms having from 1-2heteroatoms and wherein the (R)₂ in N(R)₂ may be a heterocycle havingnitrogen, all optionally substituted by F, Cl, Br, OR′, N(R′)₂, NR′COR′,or ═O; R′ is H, a straight or branched alkyl of 1-4 carbons, or phenyl;R″ is H, a straight or branched alkyl of from 1-4 carbons, F, Cl, Br,OR′, or N(R′)₂; Ar₁ is phenyl; and Ar₂ is a heterocycle of 5-6 atomshaving from 1-4 heteroatoms selected from: furan, pyrrole, thiophene,oxazole, isoxazole, thiazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole,tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, tetrahydrofuran,tetrahydrothiophene, pyrrolidine, piperazine, piperidine, morpholine,thiomorpholine, oxolane, dioxane, sulfolane: or a fused heterocycle of9-10 atoms having from 1-3 heteroatoms selected from: benzofuran,indole, indoline, benzothiophene, benzimidazole, benzthiazole,benzoxazole, quinoline, isoquinoline, cinnoline, quinazoline andquinoxaline.
 10. A compound according to claim 1 wherein: R₁ is H,methyl, ethyl, isopropyl, or t-butyl; R₂ is H or methyl; R₃ is H,(CH₂)_(n)OR, (CH₂)_(n)N(R)₂, (CH₂)_(n)NR′COR, (CH₂)_(n)CON(R)₂,(CH₂)_(n)OCON(R)₂, (CH₂)_(n)NR′CON(R), (CH₂)_(n)NR′CO₂R,(CH₂)_(n)OSO₂N(R)₂, (CH₂)_(n)NR′SO₂OR, (CH₂)_(n)NR′SO₂N(R)₂,(CH₂)_(n)OSO₂R, (CH₂)_(n)NR′SO₂R, (CH₂)_(n)SO₂R, (CH₂)_(n)NR′CSN(R)₂,(CH₂)_(n)COR, O(CH₂)_(m)OR, NR(CH₂)_(m)OR′, C(CH₃)₂OR′, F, Cl, Br, or═O; R₄, R₅ and R₆ are independently H, methyl, ethyl, OH, CH₂OH,CH₂CH₂OH, F, Cl, NH₂; any two R₄-R₆ may form a ring of 5-6 atoms havingfrom 1-2 heteroatoms; n is an integer of 0 to 3; m is an integer of 2 to4; R₇ is a straight or branched alkyl of 1-6 carbons or a carbocycle of3-6 carbons; R is H, a straight or branched alkyl of 1-4 carbons,(CH₂)_(n)Ph, or a (CH₂)_(n)heterocycle of 5-6 atoms having from 1-2heteroatoms or a heterocycle having a nitrogen, all optionallysubstituted by F, Cl, Br, OR′, N(R′)₂, NR′COR′, or ═O; R′ is H, astraight or branched alkyl of 1-4 carbons, or phenyl; R″ is H, astraight or branched alkyl of 1-4 carbons, F, Cl, Br, OR′, or N(R′)₂;Ar₁ is furan, thiophene, thiazole, pyridine, imidazole, benzofuran,benzothiophene, benzimidazole, benzthiazole, quinoline, or isoquinoline;and Ar₂ is phenyl.
 11. A compound according to claim 1 wherein: R₁ is H,methyl, ethyl, isopropyl, or t-butyl; R₂ is H or methyl; R₃ is H,(CH₂)_(n)OR, (CH₂)_(n)N(R)₂, or ═O; R₄, R₅, and R₆ are independently H,methyl, OH, CH₂OH, CH₂CH₂OH, NH₂, or F; R₇ is H, isopropyl, butyl,sec-butyl, cyclobutyl, cyclopentyl, or cyclohexyl; R is H, methyl,ethyl, phenyl, or CH₂Ph and wherein the (R)₂ of N(R)₂ may be aheterocycle having a nitrogen; R″ is H, F, or CH₃; Ar₁ is furan,thiophene, thiazole, pyridine, imidazole, benzofuran, benzothiophene,benzimidazole, benzthiazole, quinoline, or isoquinoline; and Ar₂ isphenyl.
 12. A compound according to claim 1 wherein: R₁ is H, methyl,ethyl, isopropyl, or t-butyl; R₂ is H, methyl, ethyl, or isopropyl; R₃is H, NH₂, OH, CH₂OR, CH₂N(R)₂, CH₂CON(R)₂, CH₂OSO₂N(R)₂, CH₂NHSO₂OR,CH₂NHSO₂R, CH₂OSO₂R, Cl, Br, or OCH₂CH₂OH; R₄, R₅, and R₆ areindependently H, methyl, ethyl, isopropyl, OH, NH₂, CH₂OR, CH₂N(R)₂, ═O,F, Cl, Br, or CH₂NRCOR; R₇ is methyl, ethyl, isopropyl, cyclopropyl,cyclobutyl, or cyclopentyl; R is H, methyl, ethyl, Ph, CH₂Ph, andwherein the (R)₂ in N(R)₂ may be a heterocycle having a nitrogen; R″ isH, F, or CH₃; Ar₁ is thiophene, thiazole, furan, pyridine,benzothiophene, benzofuran, benzthiazole, benzoxazole, quinoline, orisoquinoline; and AR₂ is furan, thiophene, oxazole, isoxazole,imidazale, thiazole, pyrazole, pyridine, benzofuran, benzothiophene,benzimidazole, benzthiazole, quinoline, or isoquinoline.
 13. A compoundaccording to claim 1 wherein: R₁ is isopropyl or t-butyl; R₂ is H,methyl, or ethyl; R₃ is H, NH₂, OH, CH₂OR, CH₂N(R)₂, CH₂CON(R)₂,OSO₂N(R)₂, NHSO₂OR, NHSO₂R, OSO₂R, or OCH₂CH₂OH; R₄, R₅, and R₆ areindependently H, methyl, ethyl, isopropyl, OH, NH₂, CH₂OR, CH₂N(R)₂, ═O,F, Cl, Br, or CH₂NRCOR; R₇ is methyl, ethyl, isopropyl, cyclopropyl,cyclobutyl, or cyclopentyl; R is H, methyl, ethyl, Ph, CH₂Ph, andwherein the (R)₂ in N(R)₂ may be a heterocycle containing the nitrogen;R″ is H, F, or CH₃; Ar₁ is phenyl; and Ar₂ is furan, thiophene, oxazole,isoxazole, imidazale, thiazole, pyrazole, pyridine, benzofuran,benzothiophene, benzimidazole, benzthiazole, quinoline, or isoquinoline.14. A compound according to claim 1 wherein: R₁ is isopropyl or t-butyl;R₂ is H, methyl, or ethyl; R₃ is NH₂, CH₂OH, OCH₂CH₂OH, or CH₂CH₂OH; R₄,R₅, and R₆ are independently H, NH₂, CH₂OH, ═O, methyl, ethyl, orisopropyl; R₇ is isopropyl; R″ is H, F, or CH₃, Ar₁ is phenyl; and Ar₂is furan, thiophene, imidazole, thiazole, pyrazole, or pyridine.
 15. Acompound according to claim 1 wherein: R₁ is H, methyl, ethyl,isopropyl, or t-butyl; R₂ is H or methyl; R₃ is H, CH₂OH, NH₂, or ═O;R₄, R₅, and R₆ are independently H, OH, CH₂OH, NH₂, or F; R₇ isisopropyl, sec-butyl, isobutyl, or cyclopentyl; R is H, methyl, ethyl,Ph, CH₂Ph, and wherein the (R)₂ in N(R)₂ may be a heterocycle having anitrogen; R″ is H, F, or CH₃; Ar₁ is furan, thiophene, imidazole,thiazole, pyrazole, or pyridine; and Ar₂ is phenyl.
 16. A pharmaceuticalcomposition for the treatment of infection or disease caused by aretrovirus, which comprises an amount of the compound of claim 1sufficient to provide an antivirally effective dosage of the compound inthe range of about 1 to about 50 mg/kg-day or up to 3 g per day and apharmaceutically effective carrier.
 17. A method of treatment ofinfection or disease caused by a retrovirus, which comprisesadministering to a subject in need of such treatment a compound ofclaim
 1. 18. A method of treatment of infection or disease caused by aretrovirus, which comprises administering to a subject in need of suchtreatment a compound of claim 1 in combination with an HIV reversetranscriptase inhibitor.
 19. A method of treatment of infection ordisease caused by a retrovirus, which comprises administering to asubject in need of such treatment a compound of claim 1 in combinationwith AZT.
 20. A method of treatment of infection or disease caused by aretrovirus, which comprises administering to a subject in need of suchtreatment a compound of claim 1 in combination with ddC.
 21. A method oftreatment of infection or disease caused by a retrovirus, whichcomprises administering to a subject in need of such treatment acompound of claim 1 in combination with an HIV protease inhibitor.
 22. Acompound according to claim 1 and selected from:3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-pyridin-4-yl-ethyl)-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-pyridin-3-yl-ethyl)-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-pyridin-2-yl-ethyl)-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-6-(2-furan-3-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-6-(2-furan-2-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(tetrahydro-furan-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-2-yl-ethyl)-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(5-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;(S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-isopropyl-6-phenethyl-5,6-dihydro-pyran-2-one;(S)-3-(2-Amino-5-isopropyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-isopropyl-6-phenethyl-5,6-dihydro-pyran-2-one;6-[-2-(4-Fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-3-(5-isopropyl-benzothiazol-6-ylsulfanyl)-5,6-dihydro-pyran-2-one;3-(2-Amino-5-isopropyl-benzothiazol-6-yl-sulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-phenethyl-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;(S)-3-(2-Amino-7-isopropyl-4-methyl-benzothiazol-6-yl-sulfanyl)-4-hydroxy-6-isopropyl-6-phenethyl-5,6-dihydro-pyran-2-one;(S)-3-(2-Amino-7-isopropyl-4-methyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-[2-(4-hydroxyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;(S)-(6-{4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-4-isopropyl-7-methyl-benzothiazol-2-yl)-carbamicacid methyl ester;(S)-3-(2-Amino-6-tert-butyl-benzothiazol-4-ylsulfanyl)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;(S)-3-(3-tert-Butyl-benzo[b]thiophen-2-ylsulfanyl)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(3-tert-Butyl-benzo[b]thiophen-2-yl-sulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;4-Hydroxy-3-(5-hydroxymethyl-2-isopropyl-thiophen-3-ylsulfanyl)-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiazol-5-yl)-ethyl]-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiazol-2-yl-ethyl)-5,6-dihydro-pyran-2-one:3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiazol-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;N-(4-{2-[5-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-2-isopropyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-thiazol-2-yl)-acetamide;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(5-methyl-thiazol-2-yl)-ethyl-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiazol-5-yl-ethyl)-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(2-methyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(5-methyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(2-isopropyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-isopropyl-thiazol-5-yl)-ethyl]-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(5-isopropyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-6-(2-furan-3-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxy-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(5-hydroxymethyl-thiophen-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(5-hydroxymethyl-thiophen-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(5-hydroxymethyl-thiophen-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(1H-pyrazol-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-[2-(1H-pyrazol-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-pyrimidin-5-yl-ethyl)-56-dihydro-pyran-2-one;3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-pyrimidin-5-yl-ethyl)-5,6-dihydro-pyran-2-one;6-[2-(2-Amino-pyrimidin-5-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-6-[2-(2-amino-pyrimidin-5-yl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiazol-4-yl-ethyl)-5,6-dihydro-pyran-2-one;(S)-4-Hydroxy-6-isopropyl-3-(5-isopropyl-benzothiazol-6-ylsulfanyl)-6-phenethyl-5,6-dihydro-pyran-2-one:(S)-4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-3-(5-isopropyl-benzothiazol-6-ylsulfanyl)-5,6-dihydro-pyran-2-one;3-(2-Amino-7-isopropyl-4-methyl-benzothiazol-6-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one:(S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;(S)-3-(2-Amino-5-isopropyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;(R)-3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;3-(2-Amino-5-isopropyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(2-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-pyran-2-one;3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-pyridin-3-yl-ethyl)-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(5-hydroxymethyl-thiophen-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(tetrahydro-furan-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;3-[2-tert-Butyl-4-(2-hydroxy-ethyl)-5-methyl-phenylsulfanyl]-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;5-Trifluoromethyl-pyridine-2-sulfonic acid{5-tert-butyl-4-[4-hydroxy-6-isopropyl-2-oxo-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-2H-pyran-3-ylsulfanyl]-2-methyl-phenyl}-amide;5-Trifluoromethyl-pyridine-2-sulfonic acid{5-tert-butyl-4-[4-hydroxy-6-isopropyl-2-oxo-6-(2-pyridin-3-yl-ethyl)-5,6-dihydro-2H-pyran-3-ylsulfanyl]-2-methyl-phenyl}-amide;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indol-5-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(2-methyl-thiophen-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;(S)-3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(2-methyl-thiophen-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(3-methyl-thiophen-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(3-methyl-thiophen-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiophen-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(4-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;4-Hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-3-(5-isopropyl-benzothiazol-6-ylsulfanyl)-5,6-dihydro-pyran-2-one;4-Hydroxy-3-(6-tert-butyl-indol-5-ylsulfanyl)-6-[2-(2-hydroxymethyl-phenyl)-ethyl]6-isopropyl-5,6-dihydropyran-2-one;(S)-N-[6-tert-Butyl-5-(4-hydroxy-6-isopropyl-2-oxo-6-[2-(4-hydroxy-phenyl)ethyl]-5,6-dihydro-2H-pyran-3-ylsulfanyl)-indolin-1-yl]-(4-cyanophenyl)sulfonamide;(S)-6-tert-Butyl-5-{4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-indole-1-carboxylicacid tert-butyl ester;(S)-3-(6-tert-Butyl-indol-5-yl-sulfanyl)-4-hydroxy6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;(S)-3-(6-tert-Butyl-1H-indol-5-yl-sulfanyl)-4-hydroxy-6-isopropyl-6-(2-phenethyl)-5,6-dihydro-pyran-2-one;(S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;(S)-4-Hydroxy-6-isopropyl-3-(6-isopropyl-3H-benzoimidazol-5-ylsulfanyl)-6-(2-phenethyl)-5,6-dihydro-pyran-2-one;(S)-5-(4-Hydroxy-6-isopropyl-2-oxo-6-phenethyl-5,6-dihydro-2H-pyran-3-ylsulfanyl)-6-isopropyl-1,3-dihydro-benzoimidazol-2-one;(S)-3-(6-tert-Butyl-3H-benzoimidazol-5-yl-sulfanyl)-4-hydroxy-6-isopropyl-6-(2-phenethyl)-5,6-dihydro-pyran-2-one;(S)-5-tert-Butyl-6-(4-hydroxy-6-isopropyl-2-oxo-6-(2-phenethyl)-5,6-dihydro-2H-pyran-3-ylsulfanyl)-1,3-dihydro-benzoimidazol-2-one;(S)-N-[5-tert-Butyl-6-(4-hydroxy-6-isopropyl-2-oxo-6-phenethyl-5,6-dihydro-2H-pyran-3-ylsulfanyl)-benzothiazol-2-yl]-methanesulfonamide;6-tert-Butyl-5-(4-hydroxy-6-isopropyl-2-oxo-6-phenethyl-5,6-dihydro-2H-pyran-3-ylsulfanyl)-1H-indole-2-carboxylicacid ethyl ester;6-tert-Butyl-5-(4-hydroxy-6-isopropyl-2-oxo-6-phenethyl-5,6-dihydro-2H-pyran-3-ylsulfanyl)-1H-indole-2-carboxylicacid;3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-isopropyl-6-[(2-(3-thiophenyl)-ethyl)-5,6-dihydro-pyran-2-one;(S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-[2-(3-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-[2-(3-fluoro-2-methyl-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;(S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-[2-(3,5-difluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;(S)-N-[5-tert-Butyl-6-(4-hydroxy-6-isopropyl-2-oxo-6-(2-phenethyl)-5,6-dihydro-2H-pyran-3-ylsulfanyl)-benzothiazol-2-yl]-acetamide;(S)-N-{5-tert-Butyl-6-(4-hydroxy-6-isopropyl-2-oxo-6-(2-thiophen-3-yl-ethyl-5,6-dihydro-2H-pyran-3-ylsulfanyl)-benzothiazol-2-yl}-4-cyanobenzenesulfonamide;(S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-[2-(4-fluoro-2-methyl-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;6-[2-(2-Amino-thiazol-4-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;(S)-3-(6-tert-Butyl-2.3-dihydro-1H-indol-5-ylsulfanyl)₄-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;(S)-3-(6-tert-Butyl-2,3-dihydro-1H-indol-5-ylsulfanyl)-4-hydroxy-6-isopropyl-6-[(2-(3-thiophenyl)-ethyl)-5,6-dihydro-pyran-2-one;and4-(6-tert-Butyl-5-{4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-2,3-dihydro-indole-1-sulfonyl)-benzonitrile.23. A compound according to claim 1 and selected from:3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(3-hydroxymethyl-thiophen-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(3-methyl-thiophen-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(2-methyl-thiophen-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(4-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiophen-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;3-(2-Cyclopentyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;3-(4-Amino-2-cyclopentyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(4-Amino-2-cyclopentyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(4-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(6-tert-Butyl-1-hydroxy-indan-5-ylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;and3-(6-tert-Butyl-1-hydroxy-indan-5-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one.24. A compound according to claim 1 and selected from:3-(6-tert-Butyl-1-hydroxy-indan-5-ylsulfanyl)-4-hydroxy-6-[2-(4-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-furan-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(3-hydroxymethyl-furan-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(4-hydroxymethyl-furan-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(2-methyl-furan-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(3-methyl-furan-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;and3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-furan-3-yl)-ethyl]-5,6-dihydro-pyran-2-one.25. A compound according to claim 1 and selected from:3-(2-Cyclopentyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-6-(2-furan-3-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-oneand3-(6-tert-Butyl-1-hydroxy-indan-5-ylsulfanyl)-6-(2-furan-3-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one.26. A compound according to claim 1 and selected from:3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(4-hydroxymethyl-thiazol-5-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiazol-5-yl)-ethyl]-5,6-dihydro-pyran-2-one;3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(5-hydroxymethyl-thiazol-4-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(5-methyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;6-[2-(2-Amino-thiazol-4-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;6-[2-(2-Amino-thiazol-5-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-isothiazol-4-yl-ethyl)-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-isothiazol-5-yl-ethyl)-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-isothiazol-3-yl-ethyl)-5,6-dihydro-pyran-2-one;and3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-oxazol-5-yl)-ethyl]-5,6-dihydro-pyran-2-one.27. A compound according to claim 1 and selected from:3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indol-5-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indol-5-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indazol-5-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indazol-5-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-6-[2-(1H-benzoimidazol-5-yl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;6-[2-(1H-Benzoimidazol-5-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-6-[2-(3-amino-1H-indazol-5-yl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;and6-[2-(3-Amino-1H-indazol-5-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one.28. A compound according to claim 1 and selected from:3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indol-4-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indol-4-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indazol-4-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indazol-4-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-6-[2-(3-amino-1H-indazol-4-yl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;and6-[2-(3-Amino-1H-indazol-4-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one.29. A compound according to claim 1 and selected from:3-(2-tert-Butyl-6-hydroxymethyl-5-methyl-pyridin-3-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-5-methyl-pyridin-3-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(3-tert-Butyl-2-hydroxymethyl-6-methyl-pyridin-4-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;and3(5-tert-Butyl-2-methyl-pyridin-4-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one.30. A compound according to claim 1 and selected from:3-(4-tert-Butyl-5-hydroxymethyl-thiophen-3-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;3-(4-tert-Butyl-thiophen-3-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;6-[2-(4-Amino-phenyl)-ethyl]-3-(2-tert-butyl-5-methyl-thiophen-3-ylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-5-methyl-thiophen-3-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;6-[2-(4-Amino-phenyl)-ethyl]-3-(4-tert-butyl-5-hydroxymethyl-thiophen-3-ylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;6-[2-(4-Amino-phenyl)-ethyl]-3-(3-tert-butyl-4-hydroxymethyl-5-methyl-thiophen-2-ylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;3-(3-tert-Butyl-5-methyl-thiophen-2-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(3-tert-Butyl-4-hydroxymethyl-5-methyl-thiophen-2-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;and3-(3-tert-Butyl-4-hydroxymethyl-5-methyl-thiophen-2-ylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one.31. A compound according to claim 1 and selected from:3-(6-tert-Butyl-2,3-dihydro-1H-indol-5-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;3-(6-tert-Butyl-2,3-dihydro-1H-indol-5-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(6-tert-Butyl-1H-indol-5-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;3-(6-tert-Butyl-1H-indol-5-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(7-tert-Butyl-1,2,3,4-tetrahydro-quinolin-6-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;and3-(7-tert-Butyl-1,2,3,4-tetrahydro-quinolin-6-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one.32. A compound according to claim 1 and selected from:N-(7-tert-Butyl-6-{6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-4-methyl-benzothiazol-2-yl)-acetamide;N-(7-tert-Butyl-6-{4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-4-methyl-benzothiazol-2-yl)-acetamide;N-(7-tert-Butyl-6-{6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-4-methyl-benzothiazol-2-yl)-methanesulfonamide;N-(7-tert-Butyl-6-{4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-4-methyl-benzothiazol-2-yl)-methanesulfonamide;3-(7-tert-Butyl-2-dimethylamino-4-methyl-benzothiazol-6-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;3-(7-tert-Butyl-2-dimethylamino-4-methyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(7-tert-Butyl-2-hydroxy-4-methyl-benzothiazol-6-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;and3-(7-tert-Butyl-2-hydroxy-4-methyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one.33. A compound according to claim 1 and selected from:3-(2-tert-Butyl-6-hydroxymethyl-5-methyl-pyridin-3-ylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;3-(3-tert-Butyl-2-hydroxymethyl-6-methyl-pyridin-4-ylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;3-(6-tert-Butyl-2.3-dihydro-1H-indol-5-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(6-tert-Butyl-1H-indol-5-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;3-(7-tert-Butyl-1,2,3,4-tetrahydro-quinolin-6-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;N-{7-tert-Butyl-6-[4-hydroxy-6-isopropyl-2-oxo-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-2H-pyran-3-ylsulfanyl]-4-methyl-benzothiazol-2-yl}-acetamide;N-{7-tert-Butyl-6-[4-hydroxy-6-isopropyl-2-oxo-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-2H-pyran-3-ylsulfanyl]-4-methyl-benzothiazol-2-yl}-methanesulfonamide;3-(7-tert-Butyl-2-dimethylamino-4-methyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;3-(7-tert-Butyl-2-hydroxy-4-methyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;(S)-3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-6-cyclohexyl-4-hydroxy-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;(S)-3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-6-cyclopentyl-4-hydroxy-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;(S)-3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-n-pentyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-6-cyclohexyl-4-hydroxy-6-(2-thiophen-2-yl-ethyl)-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-6-cyclopentyl-4-hydroxy-6-(2-thiophen-2-yl-ethyl)-5,6-dihydro-pyran-2-one;3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-n-pentyl-6-(2-thiophen-2-yl-ethyl)-5,6-dihydro-pyran-2-one;3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-6-cyclohexyl-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-6-cyclopentyl-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-n-pentyl-5,6-dihydro-pyran-2-one;(S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-n-pentyl-6-phenethyl-5,6-dihydro-pyran-2-one;(S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-cyclohexyl-4-hydroxy-6-phenethyl-5,6-dihydro-pyran-2-one;(S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-cyclopentyl-4-hydroxy-6-phenethyl-5,6-dihydro-pyran-2-one;(S)₄-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-propyl-3-(5-isopropyl-benzothiazol-6-ylsulfanyl)-5,6-dihydro-pyran-2-one:(S)-6-Cyclohexyl-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-3-(5-isopropyl-benzothiazol-6-ylsulfanyl)-5,6-dihydro-pyran-2-one;(S)-6-Cyclopentyl-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-3-(5-isopropyl-benzothiazol-6-ylsulfanyl)-5,6-dihydro-pyran-2-one;(S)-3-(6-tert-Butyl-1H-indol-5-yl-sulfanyl)-4-hydroxy-6-propyl-6-(2-phenethyl)-5,6-dihydro-pyran-2-one;(S)-3-(6-tert-Butyl-1H-indol-5-yl-sulfanyl)-6-cyclohexyl-4-hydroxy-6-(2-phenethyl)-5,6-dihydro-pyran-2-one;(S)-3-(6-tert-Butyl-1H-indol-5-yl-sulfanyl)-6-cyclopentyl-4-hydroxy-6-(2-phenethyl)-5,6-dihydro-pyran-2-one;(S)-3-(6-tert-Butyl-1H-indol-5-yl-sulfanyl)-4-hydroxy-6-pentyl-6-(2-phenethyl)-5,6-dihydro-pyran-2-one;(S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-[2-(3-fluoro-phenyl)-ethyl]-4-hydroxy-6-propyl-5,6-dihydro-pyran-2-one;(S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-[2-(3-fluoro-phenyl)-ethyl]-4-hydroxy-6-pentyl-5,6-dihydro-pyran-2-one;(S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-cyclohexyl-6-[2-(3-fluoro-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;and(S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-cyclopentyl-6-[2-(3-fluoro-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one.34. A compound according to claim 1 named(S)-3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one.35. A compound selected from:5-Hydroxy-6-methyl-5-[2-(4-methyl-thiazol-5-yl)-ethyl]-3-oxo-heptanoicacid methyl ester;5-Hydroxy-6-methyl-3′-oxo-5-(2-thiazol-2-yl-ethyl)-heptanoic acid methylester; 5-Hydroxy-6-methyl-3-oxo-5-(2-thiazol-4-yl-ethyl)-heptanoic acidmethyl ester;5-Hydroxy-6-methyl-3-oxo-5-(2-thiazol-5-yl-ethyl)-heptanoic acid methylester;5-Hydroxy-6-methyl-5-[2-(5-methyl-thiazol-2-yl)-ethyl]-3-oxo-heptanoicacid methyl ester;5-Hydroxy-6-methyl-5-[2-(4-methyl-thiazol-2-yl)-ethyl]-3-oxo-heptanoicacid methyl ester;5-Hydroxy-6-methyl-5-[2-(2-methyl-thiazol-4-yl)-ethyl]-3-oxo-heptanoicacid methyl ester;5-Hydroxy-6-methyl-5-[2-(5-methyl-thiazol-4-yl)-ethyl]-3-oxo-heptanoicacid methyl ester;5-Hydroxy-5-[2-(2-isopropyl-thiazol-4-yl)-ethyl]-6-methyl-3-oxo-heptanoicacid methyl ester;5-Hydroxy-5-[2-(4-isopropyl-thiazol-5-yl)-ethyl]-6-methyl-3-oxo-heptanoicacid methyl ester;5-Hydroxy-5-[2-(5-isopropyl-thiazol-4-yl)-ethyl]-6-methyl-3-oxo-heptanoicacid methyl ester;5-Hydroxy-5-[2-(4-isopropyl-thiazol-2-yl)-ethyl]-6-methyl-3-oxo-heptanoicacid methyl ester;5-[2-(2-Acetylamino-thiazol-4-yl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoicacid methyl ester;5-Hydroxy-6-methyl-3-oxo-5-(2-pyridin-2-yl-ethyl)-heptanoic acid methylester; 5-Hydroxy-6-methyl-3-oxo-5-(2-pyridin-4-yl-ethyl)-heptanoic acidmethyl ester;5-Hydroxy-6-methyl-3-oxo-5-(2-pyridin-3-yl-ethyl)-heptanoic acid methylester; 5-(2-Furan-2-yl-ethyl)-5-hydroxy-6-methyl-3-oxo-heptanoic acidmethyl ester; 5-(2-Furan-3-yl-ethyl)-5-hydroxy-6-methyl-3-oxo-heptanoicacid methyl ester;5-Hydroxy-6-methyl-3-oxo-5-[2-(tetrahydro-furan-2-yl)-ethyl]-heptanoicacid methyl ester;5-Hydroxy-6-methyl-3-oxo-5-(2-thiophen-3-yl-ethyl)-heptanoic acid methylester; 5-Hydroxy-6-methyl-3-oxo-5-(2-thiophen-2-yl-ethyl)-heptanoic acidmethyl ester;5-{2-[2-(tert-Butyl-dimethyl-silanyloxymethyl)-thiophen-3-yl]-ethyl}-5-hydroxy-6-methyl-3-oxo-heptanoicacid methyl ester;5-{2-[5-(tert-Butyl-dimethyl-silanyloxymethyl)-thiophen-3-yl]-ethyl}-5-hydroxy-6-methyl-3′-oxo-heptanoicacid methyl ester;5-{2-[5-(tert-Butyl-dimethyl-silanyloxymethyl)-thiophen-2-yl]-ethyl}-5-hydroxy-6-methyl-3-oxo-heptanoicacid methyl ester;5-Hydroxy-5-[2-(5-hydroxymethyl-thiophen-3-yl)-ethyl]-6-methyl-3-oxo-heptanoicacid methyl ester;5-Hydroxy-5-[2-(5-hydroxymethyl-thiophen-2-yl)-ethyl]-6-methyl-3-oxo-heptanoicacid methyl ester;5-Hydroxy-5-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-methyl-3-oxo-heptanoicacid methyl ester;5-[2-(3-Fluoro-2-methyl-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoicacid methyl ester;5-[2-(2-Fluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoic acidmethyl ester;5-[2-(4-Fluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoic acidmethyl ester;5-Hydroxy-6-methyl-3-oxo-5-[2-(1-trityl-1H-pyrazol-3-yl)-ethyl]-heptanoicacid methyl ester;5-Hydroxy-6-methyl-3-oxo-5-[2-(1H-pyrrol-3-yl)-ethyl]-heptanoic acidmethyl ester;5-Hydroxy-5-[2-(1H-imidazol-4-yl)-ethyl]-6-methyl-3-oxo-heptanoic acidmethyl ester;5-Hydroxy-6-methyl-3-oxo-5-(2-pyrimidin-5-yl-ethyl)-heptanoic acidmethyl ester;5-[2-(2-Amino-pyrimidin-5-yl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoicacid methyl ester;5-[2-(4-Cyano-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoic acidmethyl ester;5-Hydroxy-5-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-methyl-3-oxo-heptanoicacid methyl ester;5-{2-[2-(tert-Butyl-dimethyl-silanyloxymethyl)-phenyl]-ethyl}-5-hydroxy-6-methyl-3-oxo-heptanoicacid methyl ester;5-Hydroxy-5-[2-(1H-indol-5-yl)-ethyl]-6-methyl-3-oxo-heptanoic acidmethyl ester;5-Hydroxy-6-methyl-3-oxo-5-{2-[2-(2,2,2-trifluoro-acetylamino)-thiazol-4-yl]-ethyl}-heptanoicacid methyl ester;5-Hydroxy-6-methyl-5-[2-(4-methyl-thiophen-3-yl)-ethyl]-3-oxo-heptanoicacid methyl ester;5-Hydroxy-6-methyl-5-[2-(3-methyl-thiophen-2-yl)-ethyl]-3-oxo-heptanoicacid methyl ester;5-{2-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-thiophen-2-yl]-ethyl}-5-hydroxy-6-methyl-3-oxo-heptanoicacid methyl ester;5-Hydroxy-5-[2-(3-hydroxymethyl-thiophen-2-yl)-ethyl]-6-methyl-3-oxo-heptanoicacid methyl ester;5-[2-(2.6-Difluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoicacid methyl ester;5-[2-(3,5-Difluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoicacid methyl ester;5-[2-(2,4-Difluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoicacid methyl ester;5-[2-(3,4,5-Trifluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3′-oxo-heptanoicacid methyl ester;5-[2-(5-Fluoro-2-methyl-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoicacid methyl ester;5-[2-(2-Ethyl-5-Fluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoicacid methyl ester;5-{2-[2-(tert-Butyl-dimethyl-silanyloxymethyl)-4-fluoro-phenyl]-ethyl}-5-hydroxy-6-methyl-3-oxo-heptanoicacid methyl ester; and5-Hydroxy-5-[2-(4-fluoro-2-hydroxymethyl-phenyl)-ethyl]-6-methyl-3-oxo-heptanoicacid methyl ester.
 36. A compound selected from:4-Hydroxy-6-isopropyl-6-[2-(4-methyl-thiazol-5-yl)-ethyl]-5,6-dihydro-pyran-2-one;4-Hydroxy-6-isopropyl-6-(2-thiazol-2-yl-ethyl)-5,6-dihydro-pyran-2-one;4-Hydroxy-6-isopropyl-6-(2-thiazol-4-yl-ethyl)-5,6-dihydro-pyran-2-one;4-Hydroxy-6-isopropyl-6-(2-thiazol-5-yl-ethyl)-5,6-dihydro-pyran-2-one;4-Hydroxy-6-isopropyl-6-[2-(5-methyl-thiazol-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;4-Hydroxy-6-isopropyl-6-[2-(4-methyl-thiazol-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;4-Hydroxy-6-isopropyl-6-[2-(2-methyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;4-Hydroxy-6-isopropyl-6-[2-(5-methyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;4-Hydroxy-6-isopropyl-6-[2-(2-isopropyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;4-Hydroxy-6-isopropyl-6-[2-(4-isopropyl-thiazol-5-yl)-ethyl]-5,6-dihydro-pyran-2-one;4-Hydroxy-6-isopropyl-6-[2-(5-isopropyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;4-Hydroxy-6-isopropyl-6-[2-(4-isopropyl-thiazol-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;N-{4-[2-(4-Hydroxy-2-isopropyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-ethyl]-thiazol-2-yl}-acetamide;4-Hydroxy-6-isopropyl-6-(2-pyridin-2-yl-ethyl)-5,6-dihydro-pyran-2-one;4-Hydroxy-6-isopropyl-6-(2-pyridin-4-yl-ethyl)-5,6-dihydro-pyran-2-one;4-Hydroxy-6-isopropyl-6-(2-pyridin-3-yl-ethyl)-5,6-dihydro-pyran-2-one;6-(2-Furan-2-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;6-(2-Furan-3-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;4-Hydroxy-6-isopropyl-6-[2-(tetrahydro-furan-2-yl)-5,6-dihydro-pyran-2-one;4-Hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;4-Hydroxy-6-isopropyl-6-(2-thiophen-2-yl-ethyl)-5,6-dihydro-pyran-2-one;4-Hydroxy-6-[2-(5-hydroxymethyl-thiophen-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;4-Hydroxy-6-[2-(5-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;4-Hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;6-[2-(3-Fluoro-2-methyl-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one:δ6-[2-(2-Fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;6-[2-(4-Fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;4-Hydroxy-6-isopropyl-6-[2-(1H-pyrazol-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;4-Hydroxy-6-isopropyl-6-[2-(1H-pyrrol-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;4-Hydroxy-6-isopropyl-6-[2-(1-trityl-1H-imidazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;4-Hydroxy-6-isopropyl-6-(2-pyrimidin-5-yl-ethyl)-5,6-dihydro-pyran-2-one;6-[2-(2-Amino-pyrimidin-5-yl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;4-[2-(4-Hydroxy-2-isopropyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-ethyl]-benzonitrile;4-Hydroxy-6-isopropyl-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-5,6-dihydro-pyran-2-one;4-Hydroxy-6-[2-(1H-indol-5-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;2,2,2-Trifluoro-N-{4-[2-(4-hydroxy-2-isopropyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-ethyl]-thiazol-2-yl}-acetamide;4-Hydroxy-6-isopropyl-6-[2-(4-methyl-thiophen-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;4-Hydroxy-6-isopropyl-6-[2-(3-methyl-thiophen-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;4-Hydroxy-6-[2-(3-hydroxymethyl-thiophen-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;6-[2-(2,6-Difluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;6-[2-(3,5-Difluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;6-[2-(2,4-Difluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;6-[2-(3,4,5-Trifluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;6-[2-(5-Fluoro-2-methyl-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;6-[2-(2-Ethyl-5-Fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;6-{2-[2-(tert-Butyl-dimethyl-silanyloxymethyl)-4-fluoro-phenyl]-ethyl}-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one:and6-[2-(4-Fluoro-2-hydroxymethyl-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one.37. A compound selected from:(S)-5-Hydroxy-6-methyl-3-oxo-5-(2-thiophen-3-yl-ethyl)-heptanoic acidethyl ester;(R)-5-Hydroxy-6-methyl-3-oxo-5-(2-thiophen-3-yl-ethyl)-heptanoic acidethyl ester;5-[2-(3-Fluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoic acidethyl ester, (S) enantiomer;(R)-5-[2-(3-Fluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoicacid ethyl ester;5-[2-(3,4-Difluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoicacid ethyl ester (R and S isomers);5-Hydroxy-6-methyl-3-oxo-5-[2-(2-trifluoromethyl-phenyl)-ethyl]-heptanoicacid ethyl ester; 5-Hydroxy-6-methyl-3-oxo-5-[2(3-trifluoromethyl-phenyl)-ethyl]-heptanoic acid ethyl ester;5-Hydroxy-6-methyl-3-oxo-5-[2-(4-trifluoromethyl-phenyl)-ethyl]-heptanoicacid ethyl ester;5-[2-(3-Fluoro-5-trifluoromethyl-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoicacid ethyl ester;5-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoicacid ethyl ester;(S)-5-Hydroxy-5-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-methyl-3-oxo-heptanoicacid ethyl ester;(R)-5-Hydroxy-5-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-methyl-3-oxo-heptanoicacid ethyl ester; 5-Hydroxy-6-methyl-3-oxo-5-(2-phenyl-ethyl)-heptanoicacid ethyl ester (R and S isomers);5-[2-(4-Fluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoic acidethyl ester (S and R isomers);5-{2-[4-(tert-Butyl-dimethyl-silanyloxymethyl)-thiophen-3-yl]-ethyl}-5-hydroxy-6-methyl-3-oxo-heptanoicacid ethyl ester;(S)-5-Hydroxy-6-methyl-5-[2-(2-methyl-thiophen-3-yl)-ethyl]-3-oxo-heptanoicacid ethyl ester;(S)-5-[2-(3-Fluoro-2-methyl-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoicacid ethyl ester;(S)-5-[2-(3,5-Difluoro-2-methyl-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoicacid ethyl ester; and(S)-5-[2-(4-Fluoro-2-methyl-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoicacid ethyl ester.
 38. A compound of Formula IA

wherein R₄, R₅, and R₆ are independently H, a straight or branched alkylof 1-6 carbons, a cycloalkyl of 3-6 carbons, (CR′₂)_(n)OR,(CR′₂)_(n)N(R)₂, F, Cl, Br, CN, CF₃, ═O, (CR′₂)_(p)NR′COR,(CR′₂)_(p)SO_(p)R, (CR′₂)_(p)R, (CR′₂)_(p)OCOR, O(CR′₂)_(m)OR,NR(CR′₂)_(m)OR, (CR′₂)_(p)NR′CON(R)₂, (CR′₂)_(p)OCON(R)₂,(CR′₂)_(p)NR′CO₂R, (CR′₂)_(p)COR, (CR′₂)_(p)CO₂R, (CR′₂)_(p)CON(R)₂,(CR′₂)_(p)NR′SO₂R, (CR′₂)_(p)SO₂N(R)₂, (CR′₂)_(p)NR′SO₂OR,(CR′₂)_(p)OSO₂N(R)₂ (CR′₂)_(p)NR′SO₂N(R)₂, (CR′₂)_(p)C(NR′)N(R)₂,(CR′₂)_(p)NR′C(NR′)N(R)₂, (CR′₂)_(p)Het; any two of R₄-R₆ may togetherform a ring of 5-6 total atoms which may contain 0-3 heteroatoms; n isan integer of from 0 to 3; p is an integer from 0 to 2; R₇ is a straightor branched alkyl of 1-6 carbons or a carbocycle of 3-6 carbons; R isindependently H, a straight or branched alkyl of 1-4 carbons,(CH₂)_(n)Ph, or a (CH₂)_(n)heterocycle of 5-6 atoms containing 1-2heteroatoms and wherein the (R)₂ in N(R)₂ may form a heterocyclecontaining the nitrogen, all optionally substituted by F, Cl, Br, OR′,CN, CO₂R′, N(R′)₂, NR′COR′, CF₃, or ═O; R′ is independently H, astraight or branched alkyl of 1-4 carbons, or phenyl; R″ isindependently H, a straight or branched alkyl of 1-4 carbons, F, Cl, Br,OR′, or N(R′)₂; Ar₂ is phenyl or Het wherein Het is a heterocycle offrom 5-6 atoms having from 1-4 heteroatoms.
 39. A compound selectedfrom: 2-Amino-5-tert-butyl-benzothiazole-6-thiol;2-Amino-5-isopropyl-benzothiazole-6-thiol;5-Isopropyl-benzothiazole-6-thiol;2-Amino-7-isopropyl-4-methyl-benzothiazole-6-thiol;2-Amino-6-tert-butyl-benzothiazole-4-thiol:2-(Methyloxycarbonyl)amino-4-isopropyl-7-methyl-benzothiazole-6-thiol;3-tert-Butyl-2-mercapto-benzo[b]thiophene:5-(tert-Butyl-dimethyl-silanyloxymethyl)-2-isopropyl-3-mercapto-thiophene;(5-tert-Butyl-4-mercapto-5-methyl-phenyl)methanol;(3-tert-Butyl-4-mercapto-phenyl)methanol; and2-(5-tert-Butyl-4-mercapto-2-methyl-phenyl)-ethanol.
 40. A compoundselected from: Toluene-4-thiosulfonic acidS-(2-amino-5-tert-butyl-benzothiazol-6-yl)ester; Toluene-4-thiosulfonicacid S-(2-amino-5-isopropyl-benzothiazol-6-yl)ester;Toluene-4-thiosulfonic acid S-(5-isopropyl-benzothiazol-6-yl)ester;Toluene-4-thiosulfonic acidS-(2-amino-7-isopropyl-4-methyl-benzothiazol-6-yl)ester;Toluene-4-thiosulfonic acidS-(4-isopropyl-2-methoxycarbonylamino-7-methyl-benzothiazol-6-yl)ester;Toluene-4-thiosulfonic acidS-(2-amino-6-tert-butyl-benzothiazol-4-yl)ester; Toluene-4-thiosulfonicacid S-(3-tert-butyl-benzo[b]thiophen-2-yl)ester; Toluene-4-thiosulfonicacid S-[5-(tert-butyl-silanyloxymethyl)-2-isopropyl-thiophen-3-yl]ester;Toluene-4-thiosulfonic acidS-(2-tert-butyl-4-hydroxymethyl-phenyl)ester; Toluene-4-thiosulfonicacid S-[2-tert-butyl-4-(2-hydroxy-ethyl)-5-methyl-phenyl]ester;Benzenesulfonothioic acid, 4-methyl-,S-[2-(1,1-dimethylethyl)-5-methyl-4-[[[[(5-trifluoromethyl)-2-pyridinyl]sulfonyl]amino]phenyl]ester;6-tert-Butyl-5-(toluene-4-sulfonylsulfanyl)-indole-1-carboxylic acidtert-butyl ester;6-tert-Butyl-5-(toluene-4-sulfonylsulfanyl)-2,3-dihydro-indole-1-carboxylicacid tert-butyl ester; Toluene-4-thiosulfonic acidS-[6-tert-butyl-1-(4-cyanobenzenesulfonyl)-2,3-dihydro-1H-indol-5-yl]ester; Toluene-4-thiosulfonic acid S-(6-isopropyl-3H-benzoimidazol-5-yl)ester; Toluene-4-thiosulfonic acid S-(6-tert-butyl-3H-benzoimidzol-5-yl)ester; Toluene-4-thiosulfonic acidS-(6-tert-butyl-2-oxo-2,3-dihydro-1H-benzoimidzol-5-yl) ester;6-tert-Butyl-5-(toluene-4-sulfonylsulfanyl)-1H-indole-2-carboxylic acidethyl ester; Toluene-4-thiosulfonic acidS-(7-tert-butyl-2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-6-yl) ester;Toluene-4-thiosulfonic acidS-[5-tert-butyl-2-(4-cyanobenzenesulfonyl-amino)-benzothiazol-6-yl)]ester; Toluene-4-thiosulfonic acidS-(6-tert-butyl-2-methanesulfonylamino-benzothiazol-6-yl) ester;Toluene-4-thiosulfonic acidS-(2-acetylamino-5-tert-butyl-benzothiazol-6-yl) ester; andToluene-4-thiosulfonic acidS-(6-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) ester.
 41. Acompound selected from:3-Hydroxy-4-methyl-3-(2-thiophen-3-yl-ethyl)-pentanoic acid tert-butylester; 5-(3-Fluoro-phenyl)-3-hydroxy-3-isopropyl-pent-4-enoic acidbenzyl ester; 5-(3,4-Difluoro-phenyl)-3-hydroxy-3-isopropyl-pent-4-enoicacid benzyl ester;3-Hydroxy-3-isopropyl-5-(2-trifluoromethyl-phenyl)-pent-4-enoic acidbenzyl ester;3-Hydroxy-3-isopropyl-5-(3-trifluoromethyl-phenyl)-pent-4-enoic acidbenzyl ester;3-Hydroxy-3-isopropyl-5-(4-trifluoromethyl-phenyl)-pent-4-enoic acidbenzyl ester;5-(3-Fluoro-5-trifluoromethyl-phenyl)-3-hydroxy-3-isopropyl-pent-4-enoicacid benzyl ester;5-(4-Fluoro-3-trifluoromethyl-phenyl)-3-hydroxy-3-isopropyl-pent-4-enoicacid benzyl ester;3-Hydroxy-3-[2-(2-hydroxymethyl-phenyl)-ethyl]-4-methyl-pentanoic acidtert-butyl ester; 3-Hydroxy-4-methyl-3-(2-phenyl-ethyl)-pentanoic acidtert-butyl ester; 3-Hydroxy-3-isopropyl-5-phenyl-3′-pent-4-enoic acidbenzyl ester; 5-(4-Fluoro-phenyl)-3-hydroxy-3-isopropyl-pent-4-enoicacid benzyl ester;3-{2-[4-(tert-Butyl-dimethyl-silanyloxymethyl)-thiophen-3-yl]-ethyl}-3-hydroxy-4-methyl-pentanoicacid ethyl ester;3-Hydroxy-4-methyl-3-[2-(2-methyl-thiophen-3-yl)-ethyl]-pentanoic acidtert-butyl ester;5-(3-Fluoro-2-methyl-phenyl)-3-hydroxy-3-isopropyl-pent-4-enoic acidbenzyl ester; 5-(3,5-Difluoro-phenyl)-3-hydroxy-3-isopropyl-pent-4-enoicacid benzyl ester; and5-(4-Fluoro-2-methyl-phenyl)-3-hydroxy-3-isopropyl-pent-4-enoic acidtert-butyl ester.
 42. A compound selected from:(S)-3-Hydroxy-4-methyl-3-(2-thiophen-3-yl-ethyl)-pentanoic acid;(R)-3-Hydroxy-4-methyl-3-(2-thiophen-3-yl-ethyl)-pentanoic acid;(+/−)-3-Hydroxy-4-methyl-3-(2-thiophen-3-yl-ethyl)-pentanoic acid;3-[2-(3-Fluoro-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic acid;3-[2-(3,4-Difluoro-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic acid;3-Hydroxy-4-methyl-3-[2-(2-trifluoromethyl-phenyl)-ethyl]-pentanoicacid;3-Hydroxy-4-methyl-3-[2-(3-trifluoromethyl-phenyl)-ethyl]-pentanoicacid;3-Hydroxy-4-methyl-3-[2-(4-trifluoromethyl-phenyl)-ethyl]-pentanoicacid;3-[2-(3-Fluoro-5-trifluoromethyl-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoicacid;3-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoicacid;(S)-3-Hydroxy-3-[2-(2-hydroxymethyl-phenyl)-ethyl]-4-methyl-pentanoicacid;(R)-3-Hydroxy-3-[2-(2-hydroxymethyl-phenyl)-ethyl]-4-methyl-pentanoicacid; 3-Hydroxy-4-methyl-3-(2-phenyl-ethyl)-pentanoic acid;3-[2-(4-Fluoro-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic acid;3-{2-[4-(tert-Butyl-dimethyl-silanyloxy-methyl)-thiophen-3-yl]-ethyl}-3-hydroxy-4-methyl-pentanoicacid; 3-Hydroxy-4-methyl-3-[2-(2-methyl-thiophen-3-yl)-ethyl]-pentanoicacid;3-[2-(3-Fluoro-2-methyl-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoicacid; 3-[2-(3,5-Difluoro-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoicacid; and3-[2-(4-Fluoro-2-methyl-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoicacid.
 43. A compound selected from:(S)-4-Hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;(R)₄-Hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;6-[2-(3-Fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one(R and S isomers);6-[2-(3,4-Difluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one(R and S isomers);4-Hydroxy-6-isopropyl-6-[2-(2-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-pyran-2-one;4-Hydroxy-6-isopropyl-6-[2-(3-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-pyran-2-one;4-Hydroxy-6-isopropyl-6-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-pyran-2-one;6-[2-(3-Fluoro-5-trifluoromethyl-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;6-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;(S)-4-Hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;(R)-4-Hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;4-Hydroxy-6-isopropyl-6-(2-phenyl-ethyl)-5,6-dihydro-pyran-2-one (R andS isomers);6-[2-(4-Fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one(R and S isomers);4-Hydroxy-6-[2-(4-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;(S)-4-Hydroxy-6-isopropyl-6-[2-(2-methyl-thiophen-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;(S)-6-[2-(3-Fluoro-2-methyl-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;(S)-6-[2-(3,5-Difluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;and(S)-6-[2-(4-Fluoro-2-methyl-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one.44. A compound and the R and S isomer thereof selected from:3-[2-(3-Fluoro-phenyl)-ethyl]-3-hydroxy-1-imidazol-1-yl-4-methyl-pentan-1-one;3-Hydroxy-1-imidazol-1-yl-4-methyl-3-phenethyl-pentan-1-one;3-[2-(3,4-Difluoro-phenyl)-ethyl]-3-hydroxy-1-imidazol-1-yl-4-methyl-pentan-1-one;3-Hydroxy-1-imidazol-1-yl-4-methyl-3-[2-(2-trifluoromethyl-phenyl)-ethyl]-pentan-1-one;3-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-ethyl]-3-hydroxy-1-imidazol-1-yl-4-methyl-pentan-1-one;3-Hydroxy-1-imidazol-1-yl-4-methyl-3-[2-(3-trifluoromethyl-phenyl)-ethyl]-pentan-1-one;3-[2-(4-Fluoro-2-trifluoromethyl-phenyl)-ethyl]-3-hydroxy-1-imidazol-1-yl-4-methyl-pentan-1-one;3-Hydroxy-1-imidazol-1-yl-4-methyl-3-[2-(4-trifluoromethyl-phenyl)-ethyl]-pentan-1-one;3-[2-(4-Fluoro-phenyl)-ethyl]-3-hydroxy-1-imidazol-1-yl-4-methyl-pentan-1-one;3-Hydroxy-1-imidazol-1-yl-4-methyl-3-[2-thiophen-3-yl-ethyl)-pentan-1-one;and3-Hydroxy-3-[2-(2-hydroxymethyl-phenyl)-ethyl]-1-imidazol-1-yl-4-methyl-pentan-1-one.45. A method of treatment of infection or disease caused by aretrovirus, which comprises administering to a subject in need of suchtreatment a compound according to claim 1 and another antiretroviralagent.
 46. A method of treatment of infection or disease caused by aretrovirus, which comprises administering to a subject in need of suchtreatment a compound of claim 1 in combination with AZT and anotherantiretroviral agent.
 47. A method of treatment of infection or diseasecaused by a retrovirus, which comprises administering to a subject inneed of such treatment a compound of claim 1 in combination with ddC andanother antiretroviral agent.
 48. A method of treatment of infection ordisease caused by a retrovirus, which comprises administering to asubject in need of such treatment a compound of claim 1 in combinationwith an HIV protease inhibitor and another antiretroviral agent.